Heterocyclic compounds

ABSTRACT

The present invention provides a preventive or therapeutic agent for hyperlipidemia, comprising as an active ingredient a heterocyclic compound of the formula [1], or a pharmaceutically acceptable salt thereof: 
     R 1 -Het-D-E  [1] 
     wherein:  
     R 1  is optionally substituted aryl or aromatic heterocyclic group, Het is a divalent aromatic heterocyclic group, D is alkylene, alkenylene, alkynylene, or the like, and E is carboxy, or the like, and novel compounds among the heterocyclic compounds of the formula [1] above, which has blood triglyceride lowering effect, LDL-C lowering effect, and blood glucose lowering effect and blood insulin lowering effect, or HDL-C increasing effect or atherogenic index lowering effect all together, and hence is useful in the prevention or treatment of hyperlipidemia, arteriosclerosis, diabetes mellitus, hypertension, obesity, and the like.

TECHNICAL FIELD

[0001] The present invention is related to novel heterocyclic compoundsand pharmaceutically acceptable salts thereof.

[0002] The compounds of the present invention have blood triglyceridelowering effect, low-density lipoprotein cholesterol (hereinafter,referred to as “LDL-C”) lowering effect, and also blood glucose loweringeffect, blood insulin lowering effect, or high-density lipoproteincholesterol (hereinafter, referred to as “HDL-C”) increasing effect,atherogenic index lowering effect, which index is the ratio of non-HDL-Cto HDL-C calculated according to the formula: (totalcholesterol−HDL-C)/(HDL-C). Accordingly, the compounds of the presentinvention are useful in the prevention and treatment of coronary arterydisease, cerebral infarction, hyperlipidemia, arteriosclerosis ordiabetes mellitus.

BACKGROUND ART

[0003] The insulin resistant syndrome complicated by disorder ofcarbohydrate and/or lipid metabolism and hypertension attracts attentionas a multi-risk group of high incidence of ischemic heart disease. Theinsulin resistant syndrome is found in most of patients suffering fromobesity and non insulin-dependent diabetes mellitus (NIDDM). Themetabolic disorder of lipids herein recognized is the increase in bloodtriglycerides mainly due to the increase in chylomicron, very lowdensity lipoproteins, and remnant lipoproteins which are theintermediary metabolites thereof, and the decrease in HDL-C (Diabetes,37, 1595-1607(1988); Arch. Intern. Med., 149, 1514-1520(1989); DiabetesCare, 14, 173-194 (1991)).

[0004] Although it has often been disserted that the blood triglyceridelevel is probably an important risk factor of arteriosclerotic diseases,the clear relevance has not been established. Said level, however, hasbeen reported to be an independent risk factor of ischemic heart diseasebased on the results obtained recently using arteriography (Circulation,90, 2230-2235 (1994)).

[0005] It is well known that the HDL-C level negatively correlates toincidence of ischemic heart diseases from the results of a lot ofepidemiological researches (Circulation, 79, 8-15(1989)). HDL is thoughtto participate in the reverse cholesterol transport into liver fromextrahepatic tissues and demonstrated to have anti-arteriosclerosiseffect in animal model experiments (J. Clin. Invest., 85,1234-1241(1990); Nature, 353, 265-267(1991)).

[0006] It has been confirmed that blood total cholesterol level,especially LDL-C level, positively correlates to incidence of ischemicheart diseases and the said incidence can be decreased by lowering thelevel in a large-scale intervention trial (Lipid Research ClinicsProgram: JAMA, 251, 351(1984); Lipid Research Clinics Program: JAMA,251, 365(1984)).

[0007] Accordingly, compounds that decrease the blood triglyceride leveland LDL-C level, and also increase the HDL-C level or decrease theatherogenic index are useful as a remedy for arteriosclerosis,especially for prevention or treatment of ischemic heart diseases.Further, compounds that improve the insulin resistance are expected toreduce the blood glucose level and blood insulin level, and improve thepathological conditions of complications such as diabetes mellitus,hyperinsulinemia, hypertension and obesity, which can be risk factors ofarteriosclerotic diseases, and whereby exert effective preventive ortherapeutic activity on arteriosclerosis.

[0008] It has been heretofore known that 2-aryl-5-alkyloxazolederivatives or 2-aryl-5-alkylthiazole derivatives of the general formula(A), which have some similarity to the compounds of the presentinvention have blood lipid lowering effect or blood glucose loweringeffect.

[0009] wherein:

[0010] Ring Ar1 is aryl; V is oxygen or sulfur; Ak1 is hydrogen, alkylor haloalkyl; Ak2 is alkylene; Ak3 is alkylene, alkenylene or alkynyleneoptionally substituted by alkoxy, alkoxycarbonyl, acylthio, acylamino oraryl; Q is carboxy, 2,4-oxazolinedione-5-yl, 2,4-thiazolinedione-5-yl,or 1,2,4-oxadiazolidine-3,5-dione-2-yl; Ring Ar2 is a group of theformula [B1] or [B2].

[0011] For example, compounds included in the general formula (A),namely 2,4-thiazolidinedione derivatives, are reported to have bloodlipid lowering effect or blood glucose lowering effect in U.S. Pat. No.5,532,256, WO96/05186, JP H7-188227, A, JP S61-85372, A and U.S. Pat.No. 5,401,761.

[0012] It is described that compounds included in the general formula(A), namely 2,4-oxazolidinedione derivatives, have blood lipid loweringeffect or blood glucose lowering effect in JP H9-124623, A, WO95/18125,JP H7-165735, A and U.S. Pat. No. 5,468,762 and JP H8-92228, A.

[0013] It is described that compounds included in the general formula(A), namely 1,2,4-oxadiazolidine-3,5-dione derivatives, have blood lipidlowering effect or blood glucose lowering effect in U.S. Pat. No.5,510,360 and U.S. Pat. No. 5,480,896.

[0014] It is described that compounds included in the general formula(A), namely carboxylic acid derivatives, have blood lipid loweringeffect or blood glucose lowering effect in WO99/462325, WO98/00137,WO97/31907, WO96/38415, JP H9-323982, A, JP H8-325264, A, JP H5-507920,A, U.S. Pat. No. 5,510,360 and U.S. Pat. No. 5,480,896.

[0015] The compound of the general formula (A) is characterized in thatit has:

[0016] (1) 2-aryl-5-alkyloxazole ring or 2-aryl-5-alkylthiazole ring atone end;

[0017] (2) carboxy, 2,4-oxazolinedione-5-yl, 2,4-thiazolinedione-5-yl or1,2,4-oxadiazolidine-3,5-dione-2-yl at the other end; and

[0018] (3) an aromatic ring such as benzene represented by ring Ar2 inthe molecule.

[0019] Further, EP-A-220573 describes that oxazole derivatives of thegeneral formula (B) show antiarthritic activity.

[0020] wherein:

[0021] Ar3 is substituted phenyl or thienyl; R²³ is hydrogen or alkyl;Ak4 is alkylene having 1 to 2 carbon atoms: R²⁴ and R²⁵ are each alkyl;Q1 is carboxy, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl orN,N-dialkylcarbamoyl.

DISCLOSURE OF INVENTION

[0022] One of objectives of the present invention is to provide anexcellent preventive or therapeutic agent for hyperlipidemia,arteriosclerosis, diabetes mellitus, hypertension, obesity and the like,which has blood triglyceride lowering effect, LDL-C lowering effect andalso blood glucose lowering effect, blood insulin lowering effect, orHDL-C increasing effect, atherogenic index lowering effect.

[0023] The present inventors have intensively studied to accomplish theobjective above, and found that heterocyclic compounds of the formula[1] below met the objective and achieved the present invention.

[0024] Thus, the present invention provides a heterocyclic compound ofthe formula [1] below or pharmaceutically acceptable salts thereof, anda pharmaceutical composition comprising the same as an activeingredient.

R¹-Het-D-E  [1]

[0025] wherein:

[0026] R¹ is aryl, aromatic heterocyclic group or cycloalkyl, said arylor aromatic heterocyclic group being optionally substituted by the sameor different one to three groups selected from alkyl, haloalkyl,trihaloalkyl, alkoxy, halogen and nitro;

[0027] Het is a divalent aromatic heterocyclic group; said aromaticheterocyclic group being optionally substituted by alkyl ortrihaloalkyl;

[0028] D is alkylene, alkenylene, alkynylene or a group of the formula[2]:

[0029] wherein W is CH or nitrogen, m is an integer of 1-10 and n is aninteger of 0-9, with the proviso that m+n is an integer of 1-10; and

[0030] E is a group of the formula [3] or [4]:

[0031] wherein Y is oxygen or sulfur; R³ and R⁴ are the same ordifferent and each being hydrogen or alkyl; p is an integer of 0-2; Z iscarboxy, alkoxycarbonyl, hydroxymethyl, carbamoyl, N-hydroxycarbamoyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, cyano, 1H-5-tetrazolyl,1-alkyl-5-tetrazolyl, or 2-alkyl-5-tetrazolyl, with the proviso thatwhen D is a group of the formula [2], E is not a group of the formula[4].

[0032] Among heterocyclic compounds of the formula [1], those whereinHet is a group of the formula [5z]:

[0033] wherein R²² is hydrogen, alkyl or trihaloalkyl, D is alkylenehaving 1 to 2 carbon atoms, E is a group of the formula [4], and Y isoxygen include known compounds.

[0034] However, the present inventors have, for the first time, foundthat compounds of the formula [1] have blood triglyceride loweringeffect, LDL-C lowering effect, and also blood glucose lowering effect,blood insulin lowering effect, or HDL-C increasing effect, atherogenicindex lowering effect.

[0035] Heterocyclic compounds [1] other than those of the formula [1]wherein Het is a group of the formula [5z], D is alkylene having 1 to 2carbon atoms, R²² is hydrogen, alkyl or trihaloalkyl, E is a group ofthe formula [4] and Y is oxygen, are novel compounds that have not beendisclosed in any documents so far.

[0036] Among compounds [1] of the present invention, those wherein D isalkylene, alkenylene or alkynylene having 3-10 carbon atoms arepreferred. Another preferred compounds are those wherein Het is adivalent aromatic heterocyclic group of the formula [5]:

[0037] wherein X is oxygen, sulfur or NR⁶, R⁶ is hydrogen or alkyl, R²is hydrogen, alkyl or trihaloalkyl.

[0038] More preferred compounds among compounds [1] of the presentinvention are those wherein Het is a divalent aromatic heterocyclicgroup of the formula [5], X is oxygen, sulfur or NR⁶, R⁶ is hydrogen oralkyl, R² is hydrogen, alkyl or trihaloalkyl, and D is alkylene,alkenylene or alkynylene having 3-10 carbon atoms.

[0039] Still more preferred compounds among compounds [1] of the presentinvention are those wherein R¹ is phenyl optionally substituted by oneto two groups selected from alkyl, halogen, trihaloalkyl and alkoxy; Hetis a divalent aromatic heterocyclic group of the formula [5a]:

[0040] wherein X is as defined above and R¹⁵ is alkyl or trihaloalkyl;and D is alkylene or alkenylene having 3-7 carbon atoms.

[0041] Still furthermore preferred compounds among compounds [1] of thepresent invention are firstly those wherein R¹ is phenyl optionallysubstituted by one to two groups selected from alkyl, halogen,trihaloalkyl and alkoxy, Het is a divalent aromatic heterocyclic groupof the formula [5a], X is oxygen, sulfur or NR⁶, R⁶ is hydrogen oralkyl, R¹⁵ is alkyl or trihaloalkyl, D is alkylene or alkenylene having3-5 carbon atoms, E is a group of the formula [3], p is 1, Y is oxygen,R³ is hydrogen or alkyl and Z is carboxy or alkoxycarbonyl; and secondlythose wherein R¹ is phenyl optionally substituted by one to two groupsselected from alkyl, halogen and alkoxy, Het is a divalent aromaticheterocyclic group of the formula [5a], X is oxygen, sulfur or NR⁶, R⁶is hydrogen or alkyl, R¹⁵ is alkyl or trihaloalkyl, D is alkylene,alkenylene or alkynylene having 5-7 carbon atoms, E is a group of theformula [4], Y is oxygen, R³ and R⁴ are the same or different and eachbeing hydrogen or alkyl and Z is carboxy or alkoxycarbonyl.

[0042] Especially preferred compounds among compounds [1] of the presentinvention are firstly those wherein R¹ is phenyl optionally substitutedby one to two groups selected from alkyl and alkoxy, Het is a divalentaromatic heterocyclic group of the formula [5a], X is oxygen, R¹⁵ isalkyl, D is alkylene having 3-5 carbon atoms, E is a group of theformula [3], p is 1, Y is oxygen, R³ is alkyl and Z is carboxy; andsecondly those wherein R¹ is phenyl optionally substituted by one to twogroups selected from alkyl, halogen and alkoxy, Het is a divalentaromatic heterocyclic group of the formula [5a], X is oxygen, R¹⁵ isalkyl, D is alkylene, alkenylene or alkynylene having 5-7 carbon atoms,E is a group of the formula [4], Y is oxygen, R³ and R⁴ are the same andeach being alkyl and Z is carboxy.

[0043] Specific examples of preferred compounds [1] of the presentinvention include the following heterocyclic compounds (1)-(14) orpharmaceutically acceptable salts thereof.

[0044] (1)2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenyloxy]propionicacid

[0045] (2)c-5-[4-(5-Methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0046] (3)2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexynyloxy]propionic acid

[0047] (4)2-Isobutyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0048] (5)2-Ethyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0049] (6)2-Methyl-c-5-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0050] (7)2-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylicacid

[0051] (8)c-5-{4-[2-(4-tert-Butylphenyl)-5-methyloxazol-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylicacid

[0052] (9) 2-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propanol

[0053] (10)2-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionic acid

[0054] (11)2-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0055] (12)2-Methyl-c-5-{4-[5-methyl-2-(3-fluoro-4-methylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0056] (13)2-Methyl-c-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0057] (14)2-Methyl-c-5-{4-[5-methyl-2-(3,4-dimethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0058] For purposes of the present invention, the term “alkyl” usedherein means a straight- or branched-chain alkyl group having 1 to 7carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl,n-heptyl and isoheptyl. Straight-chain alkyl groups having 1 to 3 carbonatoms are preferred, for example, methyl, ethyl and n-propyl.

[0059] Examples of alkyl moiety of the groups “haloalkyl”,“trihaloalkyl”, “alkoxy”, “alkoxycarbonyl”, “N-alkylcarbamoyl”,“N,N-dialkylcarbamoyl”, “1-alkyl-5-tetrazolyl” and“2-alkyl-5-tetrazolyl” include alkyl groups as defined above.

[0060] The term “cycloalkyl” means a cycloalkyl group having 4 to 8carbon atoms, for example, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Cycloalkyl groups having 5 to 7 carbon atomsare preferred.

[0061] The term “alkylene” means a straight- or branched-chain alkylenegroup having 1 to 10 carbon atoms, for example, methylene, ethylene,1-methylethylene, 2-methylethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene,nonamethylene and decamethylene. Alkylene groups having 3 to 10 carbonatoms are preferred and those having 3 to 7 carbon atoms are morepreferred.

[0062] The term “alkenylene” means a straight- or branched-chainalkenylene group having 2 to 10 carbon atoms, for example, ethenylene,1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene,1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene,4-methyl-3-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene,4-hexenylene, 5-hexenylene, 1-heptenylene, 2-heptenylene, 3-heptenylene,4-heptenylene, 5-heptenylene, 6-heptenylene, 1-octenylene, 2-octenylene,3-octenylene, 4-octenylene, 5-octenylene, 6-octenylene, 7-octenylene,1-nonenylene, 2-nonenylene, 3-nonenylene, 4-nonenylene, 5-nonenylene,6-nonenylene, 7-nonenylene, 8-nonenylene, 1-decenylene, 2-decenylene,3-decenylene, 4-decenylene, 5-decenylene, 6-decenylene, 7-decenylene,8-decenylene and 9-decenylene. Alkenylene groups having 3 to 10 carbonatoms are preferred and those having 3 to 7 carbon atoms are morepreferred.

[0063] The term “alkynylene” means a straight- or branched-chainalkynylene group having 2 to 10 carbon atoms, for example, ethynylene,1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene,1-pentynylene, 2-pentynylene, 3-pentynylene, 4-pentynylene,2-methyl-3-pentynylene, 1-hexynylene, 2-hexynylene, 3-hexynylene,4-hexynylene, 5-hexynylene, 1-heptynylene, 2-heptynylene, 3-heptynylene,4-heptynylene, 5-heptynylene, 6-heptynylene, 1-octynylene, 2-octynylene,3-octynylene, 4-octynylene, 5-octynylene, 6-octynylene, 7-octynylene,1-nonynylene, 2-nonynylene, 3-nonynylene, 4-nonynylene, 5-nonynylene,6-nonynylene, 7-nonynylene, 8-nonynylene, 1-decynylene, 2-decynylene,3-decynylene, 4-decynylene, 5-decynylene, 6-decynylene, 7-decynylene,8-decynylene and 9-decynylene. Alkynylene groups having 3 to 10 carbonatoms are preferred and those having 3 to 7 carbon atoms are morepreferred.

[0064] The term “aryl” means an aryl group having 6 to 10 carbon atoms,for example, phenyl, 1-naphthyl and 2-naphthyl, and phenyl is preferred.

[0065] The term “aromatic heterocyclic ring” means a 5-6 memberedaromatic ring containing 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur, or a condensed ring thereof with a benzene ring.Examples include 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-indolyl, 2-furyl,3-furyl, 3-benzofuranyl, 2-thienyl, 3-thienyl, 3-benzothienyl,2-oxazolyl, 2-thiazolyl, 2-benzothiazolyl, 2-imidazolyl, 4-imidazolyl,2-benzimidazolyl, 1H-1,2,4-triazol-1-yl, 1H-tetrazol-5-yl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyridine-1-oxide-2-yl, pyridine-1-oxide-3-yl,pyridine-1-oxide-4-yl, 2-pyrimidinyl, 4-pyrimidinyl, 2-pyrazinyl,1,3,5-triazine-2-yl.

[0066] The term “divalent aromatic heterocyclic ring” means a 5-6membered aromatic ring containing 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, or a condensed ring thereof with a benzenering. Examples include pyrrolylene, indolylene, furanylene,benzofuranylene, thienylene, benzothienylene, oxazolylene, thiazolylene,benzothiazolylene, imidazolylene, benzimidazolylene,1H-1,2,4-triazolylene, pyridinylene, pyrimidinylene, pyrazinylene and1,3,5-triazinylene.

[0067] Examples of “halogen” include fluorine, chlorine, bromine andiodine.

[0068] Examples of halogen moiety of “haloalkyl” and “trihaloalkyl”include the halogen as defined above.

[0069] Specific examples of “trihaloalkyl” include trifluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl and 2,2,2-trichloroethyl.

[0070] The compounds [1] of the present invention can be prepared by theprocesses illustrated below or in the working Examples.

[0071] Process A

[0072] A compound [1a] of the present invention wherein E is a group ofthe formula [3] and Z is alkoxycarbonyl can be prepared by reacting acompound [11] and a compound [22].

[0073] wherein R¹, Het, D, Y, p and R³ have the same meaning as definedabove, and R¹¹ is alkyl.

[0074] Generally, the reaction can be conducted in an appropriatesolvent (e.g., a polar solvent such as acetonitrile orN,N-dimethylformamide (DMF), ether solvent such as tetrahydrofuran (THF)or diethyl ether, halogenated hydrocarbon solvent such as chloroform ordichloromethane, ester solvent such as methyl acetate or ethyl acetate,hydrocarbon solvent such as benzene, toluene or n-hexane, or a mixturethereof), in the presence of a Lewis acid (e.g., boron trifluorideetherate complex) at −20 to 150° C. Although the reaction time variesdepending on the kind of the compound [11] and compound [22], orreaction temperature, it would be suited to be between 30 minutes and 24hours in general. The compound [22) is preferably used in an amount of 1to 5 moles to one mole of the compound [11].

[0075] Process B

[0076] A compound [1b] of the present invention wherein E is a group ofthe formula [4] and Z is carboxy can be prepared by reacting a compound[12] and a compound [13], and then treating with acid.

[0077] wherein R¹, Het, Y, R³ and R⁴ have the same meaning as definedabove, L is a leaving group such as halogen, methanesulfonyloxy ortoluenesulfonyloxy, T is halogen, R¹³ and R¹⁴ are the same or differentand each being alkyl, D¹ is alkylene, alkenylene or alkynylene havingfewer carbon atoms than that for D by one atom (D has the same meaningas defined above).

[0078] The compound [14] can be prepared by, in general, treating acompound [13] with a metal reagent such as butyl lithium or magnesiumfollowed by reacting with a compound [12] in the presence of copperiodide or copper bromide at −80 to 150° C., in an aprotic solvent (e.g.,a polar solvent such as acetonitrile or N,N-dimethylformamide (DMF),ether solvent such as tetrahydrofuran (THF) or diethyl ether,halogenated hydrocarbon solvent such as chloroform or dichloromethane,ester solvent such as methyl acetate or ethyl acetate, hydrocarbonsolvent such as benzene, toluene or n-hexane, or a mixture thereof).Although the reaction time varies depending on the kind of the compound[12], compound [13] and metal reagent, or reaction temperature, it wouldbe suited to be between 30 minutes and 24 hours in general. The metalreagent and the compound [12] is preferably used in an amount of 1 to1.2 moles to one mole of the compound [13].

[0079] The compound [1b] can be, in general, prepared by treating acompound [14] with an acid (e.g., hydrochloric acid) in an alcoholsolvent (e.g., methanol or ethanol) at −80 to 80° C. for 5 minutes to 24hours.

[0080] Process C

[0081] A compound [1c] wherein D is alkenylene which adjoins Het at theunsaturated bond moiety can be prepared by Wittig reaction using acompound [15] and compound [16].

[0082] wherein R¹, Het, E and T have the same meaning as defined above,Ph is phenyl, D² is alkenylene having fewer carbon atoms than that for Dby two atoms (D has the same meaning as defined above), or a group ofthe formula [2] above.

[0083] The reaction can be conducted, in general, in a solvent similarto that used in PROCESS A above in the presence of a base (e.g., sodiumhydroxide) at −20 to 150° C. Although the reaction time varies dependingon the kind of the compound [15] and compound [16], or reactiontemperature, it would be suited to be between 30 minutes and 24 hours ingeneral. The compound [16] is preferably used in an amount of 1 to 1.2moles to one mole of the compound [15].

[0084] Process D

[0085] A compound [1d] of the present invention wherein Het is a groupof the formula [5a]:

[0086] wherein X and R¹⁵ have the same meaning as defined above, E is agroup of the formula [3] or [4], and Z is alkoxycarbonyl can also beprepared by reacting a compound [17] with phosphorus oxychloride,thionyl chloride, phosphorus pentoxide, a Davy reagent methyl(2,4-bis(methylthio)-1,3-dithia-2.4-diphosphetane-2,4-disulfide), aLawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide),ammonia or alkylamine. When phosphorus oxychloride, thionyl chloride orphosphorus pentoxide is used, oxazole derivatives can be obtained, whena Davy reagent methyl or a Lawesson's reagent is used, thiazolederivatives can be obtained, and when ammonia or alkylamine is used,imidazole derivatives can be obtained.

[0087] wherein R¹, D and R¹⁵ have the same meaning as defined above, andE¹ is a group of the formula [31] or [41]:

[0088] wherein R³, R⁴, R¹¹, Y and p have the same meaning as definedabove.

[0089] Generally, the reaction can be conducted in an appropriatesolvent (e.g., a hydrocarbon solvent such as benzene, toluene or xylene,a halogenated hydrocarbon solvent such as chloroform or dichloromethane,a polar solvent such as N,N-dimethylformamide (DMF), ether solvent suchas tetrahydrofuran (THF) or diethyl ether, or acetic acid, or a mixturethereof) at −10 to 200° C. Although the reaction time varies dependingon the kind of the reagent (e.g., phosphorus oxychloride, Lawesson'sreagent, alkylamine), the kind of compound [17], or reactiontemperature, it would be suited to be between 30 minutes and 24 hours ingeneral. The phosphorus oxychloride, thionyl chloride, phosphoruspentoxide, Davy reagent methyl, Lawesson's reagent, ammonia oralkylamine is preferably used in an amount of 1 to 10 moles to one moleof the compound [17].

Process E

[0090] A compound [1e] of the present invention wherein Het is a groupof the formula [5a] above, E is a group of the formula [4] and Z isalkoxycarbonyl can also be prepared by reacting a compound [18] and acompound [19].

[0091] wherein R¹, R³, R⁴, R¹¹, R¹⁵, X, Y, L and D¹ have the samemeaning as defined above.

[0092] The reaction can be conducted, in general, in a solvent similarto that used in PROCESS A above in the presence of a base (e.g., sodiumhydride or sodium carbonate) at −20 to 150° C. Although the reactiontime varies depending on the kind of the compound [18] and compound[19], or reaction temperature, it would be suited to be between 30minutes and 24 hours in general. The compound [19] is preferably used inan amount of 1 to 1.2 moles to one mole of the compound [18].

Process F

[0093] A compound [1d] of the present invention wherein Het is a groupof the formula [5a] above can also be prepared by reacting a compound[20] and a compound [21].

[0094] wherein R¹, R¹⁵, D, E¹ and X have the same meaning as definedabove, and L¹ is chlorine or bromine.

[0095] The reaction can be conducted, in general, in the absence of asolvent or in a solvent similar to that used in PROCESS A above in thepresence of a base (e.g., sodium hydride or sodium carbonate) at −20 to150° C. Although the reaction time varies depending on the kind of thecompound [20] and compound [21], or reaction temperature, it would besuited to be between 30 minutes and 24 hours in general. The compound[21] is preferably used in an amount of 1 to 1.2 moles to one mole ofthe compound [20].

[0096] Process G

[0097] A compound [1h] of the present invention wherein Z is carboxy canbe prepared by hydrolyzing a compound [1g] of the present inventionwherein Z is alkoxycarbonyl.

[0098] A compound [1g] of the present invention can be prepared byallowing a compound [1h] of the present invention to condense with analcohol [73] or to react with an alkylating agent.

[0099] Further, a compound [1i] of the present invention wherein z iscarbamoyl, N-hydroxycarbamoyl, N-alkylcarbamoyl or N,N-dialkylcarbamoylcan be prepared by reacting a compound [1h] of the present inventionwith a compound [82], i.e., ammonia, hydroxylamine, alkylamine ordialkylamine.

[0100] wherein R¹, R¹¹, Het, D and E¹ have the same meaning as definedabove; R⁷ is hydrogen and R⁸ is hydrogen, hydroxy or alkyl, or R⁷ isalkyl and R⁸ is alkyl; E² is a group of the formula [32] or [42]; E³ isa group of the formula [33] or [43]:

[0101] wherein R³, R⁴, R⁷, R⁸, Y and p have the same meaning as definedabove.

[0102] The hydrolysis of compound [1g] can generally be conducted in amixed solvent of an alcohol solvent such as methanol, ethanol,isopropanol or tert-butyl alcohol and water in the presence of an acid(e.g., hydrochloric acid, sulfuric acid or p-toluenesulfonic acid) or abase (e.g., sodium hydroxide or potassium hydroxide) at −20 to 150° C.Although the reaction time varies depending on the kind of compound[1g], or reaction temperature, it would be suited to be between 30minutes and 24 hours in general. The acid or base is preferably used inan amount of 1 to 20 moles to one mole of the compound [1g].

[0103] The condensation between a compound [1h] and an alcohol [73] canbe, in general, conducted using the alcohol as a solvent in the presenceof an acid (e.g., hydrochloric acid, sulfuric acid or p-toluenesulfonicacid) at −20 to 150° C. Although the reaction time varies depending onthe kind of compound [1h], kind of alcohol, or reaction temperature, itwould be suited to be between 30 minutes and 24 hours in general. Theacid is preferably used in an amount of 0.1 to 1.2 moles to 1 mole ofcompound [1h].

[0104] The said condensation reaction can also be conducted in a solventsimilar to that used in PROCESS A above in the presence of a condensingagent (e.g., N,N′-dicyclohexylcarbodiimideor 1,1′-carbonyldiimidazole)at −20 to 150° C. Although the reaction time varies depending on thekind of compound [1h], kind of alcohol or condensing agent, or reactiontemperature, it would be suited to be between 30 minutes and 24 hours ingeneral. The condensing agent is preferably used in an amount of 1 to1.2 moles to 1 mole of compound [1h].

[0105] The reaction between a compound [1h] and an alkylating agent(e.g., trimethylsilyldiazomethane/methanol, methyl iodide) can beconducted in a solvent similar to that used in PROCESS A above at −20 to150° C. Although the reaction time varies depending on the kind ofcompound [1h], kind of alkylating agent, or reaction temperature, itwould be suited to be between 30 minutes and 24 hours in general. Thealkylating agent is preferably used in an amount of 1 to 2 moles to 1mole of compound [1h].

[0106] The reaction between a compound [1h] and a compound [82] can beconducted in a manner similar to the said condensing reaction between acompound [1h] and an alcohol [73]. Further, a compound [1i] of thepresent invention can be prepared by reacting a reactive derivative ofcompound [1h] and a compound [82] by a method known in the art. Examplesof reactive derivatives include reagents generally used in amidationsuch as acid halides (acid chlorideor acid bromide), mixed acidanhydride, activated amide, and the like.

[0107] For example, when acid halide is used as a reactive derivative,the reaction can be conducted in an aprotic solvent (e.g., a polarsolvent such as acetonitrile or N,N-dimethylformamide (DMF), ethersolvent such as tetrahydrofuran (THF) or diethyl ether, halogenatedhydrocarbon solvent such as chloroform or dichloromethane, hydrocarbonsolvent such as benzene, toluene or n-hexane, or a mixture thereof) inthe presence of a base (e.g., potassium carbonate, sodium carbonate,sodium hydrogen carbonate, potassium hydrogen carbonate, pyridine,4-dimethylaminopyridine, triethylamine, sodium hydroxide) at −20 to 100°C. Although the reaction time varies depending on the kind of acidhalide and compound [82], or reaction temperature, it would be suited tobe between 30 minutes and 24 hours in general. The compound [82] ispreferably used in an amount of 1 to 1.2 moles to one mole of the acidhalide.

[0108] Process H

[0109] A compound [1k] of the present invention wherein D is alkenylenewhich adjoins Het at the unsaturated bond moiety can also be prepared bydehydrogenating a compound [1j] of the present invention wherein D isalkylene.

[0110] Further, a compound [1k] of the present invention can also beprepared by hydrogenating a compound [1m] of the present inventionwherein D is alkynylene which adjoins Het at the unsaturated bondmoiety.

[0111] A compound [1j] of the present invention can also be prepared byhydrogenating a compound [1k] of the present invention.

[0112] wherein R¹, Het, D² and E¹ have the same meaning as definedabove.

[0113] The dehydrogenation of a compound [1j] can be conducted byreacting the compound with N-bromosuccinimide (NBS) orN-chlorosuccinimide (NCS) in a solvent similar to that used in PROCESS Aabove at −20 to 150° C., and then reacting with a base (e.g., sodiumhydroxide or potassium hydroxide) in alcohol solvent such as methanol orethanol. Although the reaction time varies depending on the kind ofcompound [1j], or reaction temperature, it would be suited to be between30 minutes and 24 hours in general. The NBS NCS, or a base is preferablyused in an amount of 1 to 1.2 moles to 1 mole of compound [1j].

[0114] The hydrogenation of a compound [1m] can be conducted in analcohol solvent (e.g., methanol or ethanol) in the presence of palladiumcatalyst (e.g., palladium-calcium carbonateor palladium-carbon) at −20to 150° C. Although the reaction time varies depending on the kind ofcompound [1m], palladium catalyst, or reaction temperature, it would besuited to be between 30 minutes and 24 hours in general. The palladiumcatalyst is preferably used in an amount of 0.05 to 0.5 moles to 1 moleof compound [1m].

[0115] The hydrogenation of a compound [1k] can be conducted in analcohol solvent (e.g., methanol or ethanol) in the presence of palladiumcatalyst (e.g., palladium-carbon) at −20 to 150° C. Although thereaction time varies depending on the kind of compound [1k], palladiumcatalyst, or reaction temperature, it would be suited to be between 30minutes and 24 hours in general. The palladium catalyst is preferablyused in an amount of 0.05 to 0.2 moles to 1 mole of compound [1k].

[0116] Process I

[0117] A compound [1n] of the present invention wherein Z ishydroxymethyl can be prepared by reducing a compound [1g] of the presentinvention wherein Z is alkoxycarbonyl.

[0118] wherein R¹ Het, D, E¹ have the same meaning as defined above, E⁴is a group of the following formula [34] or [44]:

[0119] wherein R³, R⁴, Y and p have the same meaning as defined above.

[0120] The reaction can be conducted in the presence of a reducing agent(e.g., lithium aluminium hydride, sodium borohydrideor lithiumdiisobutylalminium hydride) in an appropriate solvent (e.g., ethersolvent such as tetrahydrofuran (THF) or diethyl ether, a polar solventsuch as N,N-dimethylformamide (DMF) or dimethyl sulfoxide, an alcoholsolvent such as methanol, ethanol or isopropanol, or a mixture thereof)at −20 to 100° C. Although the reaction time varies depending on thekind of the compound [1g] or reaction temperature, it would be suited tobe between 30 minutes and 24 hours in general. The reducing agent ispreferably used in an amount of 0.5 to 2 moles to one mole of thecompound [1g].

[0121] Process J

[0122] A compound [1q] wherein E is a group of the formula [3] or [4]and Z is cyano can be prepared from a compound [1p] of the presentinvention wherein Z is carbamoyl or N-hydroxycarbamoyl.

[0123] wherein R¹, Het and D have the same meaning as defined above, E⁵is a group of the formula [35] or [45], and E⁶ is a formula of the group[36] or [46]:

[0124] wherein R³, R⁴, Y and p have the same meaning as defined above,and R¹² is hydrogen or hydroxy.

[0125] When the starting compound wherein Z is carbamoyl, i.e., R¹² ishydrogen, is used, it can generally be treated with a dehydrating agent(e.g., phosphorus pentoxide, thionyl chloride, trifluoroacetic anhydrideor N,N′-dicyclohexylcarbodiimide) without a solvent or in a solventsimilar to that used in PROCESS A above. Although the reaction timevaries depending on the kind of compound [1p], kind of dehydratingagent, or reaction temperature, it would be suited to be between 30minutes and 24 hours in general. The dehydrating agent is preferablyused in an amount of 1 to 5 moles to 1 mole of compound [1p].

[0126] When the starting compound wherein Z is N-hydroxycarbamoyl, i.e.,R¹² is hydroxy, is used, the reaction can be conducted in accordancewith the method of A. Liguori et al., Synthesis, 168(1987).

[0127] Process K

[0128] A compound [1r] of the present invention wherein E is a group ofthe formula [3] or [4] and Z is 1H-5-tetrazolyl can be prepared byreacting a compound [1q] of the present invention wherein Z is cyanowith an azide.

[0129] wherein R¹, Het, D and E⁶ have the same meaning as defined above,and E⁷ is a group of the formula [37] or [47]:

[0130] wherein R³, R⁴, Y and p have the same meaning as defined above.

[0131] The reaction can generally be conducted in an appropriate solvent(e.g., an alcohol solvent such as methanol, ethanol or methoxyethanol,hydrocarbon solvent such as benzene or toluene, halogenated hydrocarbonsolvent such as chloroform or dichloromethane, polar solvent such asN,N-dimethylformamide (DMF) or dimethyl sulfoxide, ether solvent such astetrahydrofuran (THF), or a mixture thereof) in the presence of an azide(e.g., sodium azide, azide trimethylsilane, or azide trimethyltin) at 0to 200° C. The reaction can be conducted in the coexistence of anadditive such as lithium chloride or ammonium chloride. Although thereaction time varies depending on the kind of the compound [1q], kind ofthe azide, or reaction temperature, it would be suited to be between 30minutes and 100 hours in general.

[0132] Process L

[0133] A compound [1s] of the present invention wherein E is a group ofthe formula [3] or [4] and Z is 1-alkyl-5-tetrazolyl or2-alkyl-5-tetrazolyl can be prepared by reacting a compound [1r] of thepresent invention wherein Z is 1H-5-tetrazolyl with an alkylating agent.

[0134] wherein R¹, Het, D, E⁷ and L have the same meaning as definedabove, R²⁰ is alkyl and E⁸ is a group of the formula [38] or [48]:

[0135] wherein R³, R⁴, Y, p and R²⁰ have the same meaning as definedabove.

[0136] The reaction can be conducted, for example, in a solvent similarto that used in PROCESS A above in the presence of an alkylating agent(e.g., alkyl halide, alkyl mesylate or alkyl tosylate) and a base at 0to 150° C. Examples of a base to be used includes an organic amine(e.g., pyridine or triethylamine), a metal hydride (e.g., sodiumhydride), an inorganic base (e.g., potassium carbonate, sodium hydrogencarbonate or sodium hydroxide). Although the reaction time variesdepending on the kind of the starting material, or reaction temperature,it would be suited to be between 30 minutes and 100 hours in general.The halogenating agent and the base are each used in an amount of 1 to10 moles preferably 1 to 5 moles to one mole of the compound [1r].

[0137] The present compounds may exist as tautomers. The presentinvention encompasses respective tautomers within the scope of theinvention.

[0138] The present compounds may exist as geometric isomers due to thepresence of a double bond. The present invention encompasses respectivegeometric isomers and a mixture thereof.

[0139] The present compounds may exist as stereoisomers due to thepresence of an asymmetric carbon atom. The present invention encompassesrespective stereoisomers and a mixture thereof.

[0140] Such a stereoisomer can be obtained from a mixture by means ofsilica gel column chromatography.

[0141] Further, said stereoisomer can be obtained from a mixture byliquid chromatography using a column for separating an optically activesubstance (e.g., CHIRALCEL® OD, CHIRALCEL® OF, DAICEL, Ltd.).

[0142] When the compound of the present invention has a carboxy group,it can be converted into a pharmaceutically acceptable salt by a knownmethod. Examples of the pharmaceutically acceptable salt includealkaline metal salt (e.g., sodium salt, potassium salt, etc.), alkalineearth metal salt (e.g., calcium salt, magnesium salt, etc.), ammoniumsalt, salt with an organic amine (e.g., triethyl amine, lysine,arginine, etc.), and the like.

[0143] For example, an alkaline metal salt of the present compound canbe prepared by adding one equivalent of sodium hydroxide or potassiumhydroxide to the present compound preferably in an alcoholic solvent.

[0144] An alkaline earth metal salt of the present compound can beprepared by dissolving the alkaline metal salt obtained according to theabove-mentioned method into water, methanol, ethanol or a mixed solventthereof and adding one equivalent of calcium chloride or the like.

[0145] When the present compound is basic, it can be converted into apharmaceutically acceptable salt by a know method. Examples of saltincludes a salt with an inorganic acid such as hydrochloric acid,sulfuric acid, nitric acid, phosphoric acid, or the like; or a salt withan organic acid such as fumaric acid, maleic acid, methanesulfonic acid,p-toluenesulfonic acid, or the like. For example, a hydrochloride of thepresent compound can be prepared by adding one equivalent ofhydrochloric acid to the present compound, preferably in an alcoholsolvent.

[0146] The present compound or a salt thereof can be isolated andpurified from the reaction mixture of the reaction above by any ofconventional methods; for example, extraction, concentration,neutralization, filtration, recrystallization, column chromatography,thin-layer chromatography, and the like.

[0147] The compounds used as the starting material in the preparation ofthe present compounds are known compounds, or can be, for example,prepared according to the processes illustrated below or those describedin the Reference Examples.

[0148] Preparation of Compounds [11a] and [11b]

[0149] Among compounds of the formula [11] used as the starting materialin the PROCESS A, those wherein D is CH₂-D¹ and Y is oxygen (compound[11a]) or sulfur (compound [11b]) can be prepared according to thefollowing processes.

[0150] wherein R¹, Het, D¹ p, T and L have the same meaning as definedabove.

[0151] The compound [51] can be obtained by dehydrating condensation ofa compound [50] and acetone in an appropriate solvent (e.g., benzene) inthe presence of an acidic catalyst (e.g., p-toluenesulfonic acid).

[0152] The compound [52] can be obtained by adding tri-n-butylphosphineand copper iodide to the compound [51] in an appropriate solvent (e.g.,anhydrous tetrahydrofuran) and allowing to react with the compound [12]at temperature −60° C. or below. Magnesium can be used in place oftri-n-butylphosphine and copper iodide.

[0153] The compound [11a] can be obtained by treating the compound [52]in an appropriate solvent (e.g., ethanol or methanol) under an acidiccondition (e.g., in the presence of pyridinium p-toluenesulfonate) at 0to 100° C.

[0154] The compound [11b] can be obtained by converting the compound[11a] into a bromide through reaction with a brominating agent (e.g.,triphenylphosphine/carbon tetrabromide or phosphorus tribromide) in anappropriate solvent (e.g., tetrahydrofuran, benzene), and then reactingwith thiourea at −20 to 100° C.

[0155] Process of Compound [50a]

[0156] Among the compounds of the formula [50] used as the startingmaterial in the preparation of the compound [11a] above, compounds [50a]wherein p is 1 can be prepared according to the following processes.

[0157] wherein D¹ and T have the same meaning as defined above, and R¹⁸is alkyl.

[0158] The compound [55] can be obtained by reacting a compound [53] anda malonic acid diester [54] in an appropriate solvent (e.g., anhydroustetrahydrofuran) in the presence of a basic catalyst (e.g., sodiumhydride) at −50 to 100° C.

[0159] The compound [50a] can be obtained by subjecting the compound[55] to the reaction in a manner similar to that described in PROCESS Iabove.

[0160] Process of Compound [50b]

[0161] Among the compounds of the formula [50] used as the startingmaterial in the preparation of the compound [11a] above, compounds [50b]wherein p is 0 can be prepared according to the following processes.

[0162] wherein D¹ and T have the same meaning as defined above.

[0163] The compound [50b] can be obtained by reacting a compound [56]with an oxidizing agent (e.g., osmium tetroxide) in an appropriatesolvent (e.g., diethyl ether) at −20 to 50° C.

[0164] Preparation of Compound [50c]

[0165] Among the compounds of the formula [50] used as the startingmaterial in the preparation of the compound [11a] above, compounds [50c]wherein p is 2 can be prepared according to the following processes.

[0166] wherein D¹, T and R¹⁸ have the same meaning as defined above.

[0167] The compound [59] can be obtained by reacting a compound [55] anda compound [58] in an appropriate solvent (e.g., tetrahydrofuran orethanol) in the presence of a base (e.g., sodium alkoxide such as sodiumethoxide or sodium hydride) at −20° C. to room temperature.

[0168] The compound [60] can be obtained by subjecting the compound [59]to hydrolysis in a manner similar to that described in PROCESS G abovefollowed by decarboxylation reaction by heating at 50 to 150° C. in theabsence of a solvent or in an appropriate solvent (e.g., xylene,toluene, ethyl acetate, or a mixture thereof).

[0169] The compound [50c] can be obtained by subjecting the compound[60] to reduction in a manner similar to that described in PROCESS Iabove.

[0170] The compound [50c] can also be obtained by subjecting thecompound [60] to esterification in a conventional manner followed byreduction in a manner similar to that described above.

[0171] Preparation of Compounds [11c] and [11d]

[0172] Among compounds of the formula [11] used as the starting materialin the PROCESS A, those wherein Het is a group of the formula [5a], D isD¹ —CH₂, p is 1, and Y is oxygen (compound [11c]) or sulfur (compound[11d]) can be prepared according to the following processes.

[0173] wherein R¹, R¹⁵, R¹⁸, D¹, X and L have the same meaning asdefined above.

[0174] The compound [81] can be obtained by reacting a compound [18] anda malonic acid dialkyl in an appropriate solvent (e.g., tetrahydrofuranor ethanol) in the presence of a base (e.g., sodium alkoxide such assodium ethoxide or sodium hydride) at −20° C. to room temperature.

[0175] The compound [11c] can be obtained by subjecting the compound[81] to the reaction in a manner similar to that described in PROCESS Iabove.

[0176] The compound [11d] can be obtained by subjecting the compound[11c] to the reaction similar to that wherein the compound [11b] isobtained from the compound [11a].

[0177] Preparation of Compound [13]

[0178] The compound [13] used as the starting material in the PROCESS Bcan be prepared according to the following processes.

[0179] wherein R³, R⁴, R¹¹ R¹³, R¹⁴, D¹, Y and T have the same meaningas defined above.

[0180] The compound [61] can be obtained by reacting the compound [19]and compound [53] in a manner similar to that described in the PROCESSE.

[0181] The compound [62] can be obtained by treating the compound [61]in a manner similar to the hydrolysis described in the PROCESS G above.

[0182] The compound [13] can be obtained by reacting the compound [62]and compound [63] in an appropriate solvent (e.g., toluene) at 90 to150° C.

[0183] Preparation of Compound [16]

[0184] The compound [16] used as the starting material in the PROCESS Ccan be prepared according to the following processes.

[0185] wherein E, D², T and Ph have the same meaning as defined above.

[0186] The compound [16] can be obtained by reacting the compound [64]and triphenylphosphine in a solvent similar to that described in thePROCESS A above at −20 to 150° C.

[0187] Preparation of Compound [17]

[0188] The compound [17] used as the starting material in the PROCESS Dcan be prepared according to the following processes.

[0189] wherein R¹, R¹¹, R¹⁵, R¹⁸, E¹, E², D and T have the same meaningas defined above.

[0190] The compound [67] can be obtained by reacting the compound [65]and compound [66] in a solvent similar to that described in the PROCESSA above in the presence of a base (e.g., triethylamine ordimethylaniline) at −20 to 150° C.

[0191] The compound [69] can be obtained from the compound [67] and [68]in a manner similar to that used for the preparation of the compound[59] above.

[0192] The compound [70] can be obtained from the compound [69] in amanner similar to that used for the preparation of the compound [60]above.

[0193] The compound [72] can be obtained by allowing the compound [70]and compound [71] to react in an appropriate solvent (e.g., pyridine) at50 to 110° C., and then at 30 to 100° C. after addition of water.

[0194] The compound [17] can be obtained by subjecting the compound [72]to the reaction similar to that described in the PROCESS G above whereinthe compound [1g] is obtained from the compound [1h].

[0195] Preparation of Compound [68a]

[0196] Among compounds of the formula [68] used as the starting materialin the preparation of the compound [17]above, the compound [68a] whereinE¹ is a group of the formula [31] can be prepared according to thefollowing processes.

[0197] wherein D, T, Y, p, R³ and R¹¹ have the same meaning as definedabove.

[0198] The compound [68a] can be obtained by reacting the compound [22]and compound [74] which can be prepared in the same manner as thecompound [50], in a manner similar to that described in the PROCESS Aabove.

[0199] Preparation of Compound [68b]

[0200] Among compounds of the formula [68] used as the starting materialin the preparation of the compound [17] above, compounds [68b] whereinE¹ is a group of the formula [41] can be prepared according to thefollowing processes.

[0201] wherein D, T, Y, R³, R⁴ and R¹¹ have the same meaning as definedabove.

[0202] The compound [68b] can be obtained by reacting the compound [19]and the compound [75] in a manner similar to that described in thepreparation of compound [61] above.

[0203] Preparation of Compound [18]

[0204] The compound [18] used as the starting material in the PROCESS Ecan be prepared according to the following processes.

[0205] wherein R¹, R¹¹, R¹⁵, X, D¹ and L have the same meaning asdefined above.

[0206] The compound [77] can be obtained from the compound [76] obtainedby a method as described in the PROCESS D above, in accordance with amethod similar to that described in the PROCESS I above.

[0207] The compound [18] can be obtained by reacting the compound [77]and a brominating agent (e.g., triphenylphosphine/carbon tetrabromide)or a sulfonyl halide (e.g., p-toluenesulfonyl chloride) in a solventsimilar to that described in the PROCESS A above at −20 to 150° C.

[0208] Preparation of Compound [21]

[0209] The compound [21] used as the starting material in the PROCESS Fcan be prepared according to the following processes.

[0210] wherein R¹⁵, D, E¹ and L¹ have the same meaning as defined above.

[0211] The compound [79] can be obtained by reacting a compound [78]with an oxidizing agent (e.g., m-chloroperbenzoic acid) in anappropriate solvent (e.g., dichloromethane) at −10° C. to roomtemperature.

[0212] The compound [80] can be obtained by reacting the compound [79]with lithium chloride or lithium bromide in an appropriate solvent(e.g., anhydrous tetrahydrofuran) at room temperature.

[0213] The compound [21] can be obtained by reacting the compound [80]with a Jones reagent (e.g., conc. sulfuric acid and chromium (VI) oxide)at room temperature.

[0214] The compound of the present invention has blood triglyceridelowering effect and LDL-C lowering effect, and therefore is useful inthe prevention and treatment of diseases such as hyperlipidemia, whichare caused by elevated blood triglyceride level or total cholesterollevel.

[0215] The present compounds showed various effects in KK-A^(y) mouse,NIDDM model animal which develops hypertriglyceridemia, hyperglycemiaand hyperinsulinemia, such as blood triglyceride lowering effect, verylow density lipoprotein cholesterol (hereinafter, referred to as“VLDL-C”) lowering effect, LDL-C lowering effect, and blood glucoselowering effect, blood insulin lowering effect, or HDL-C increasingeffect or atherogenic index lowering effect, and are expected to be anespecially excellent preventive or therapeutic agent forarteriosclerosis in comparison with known compounds. Further, thetoxicity of the present compounds is low enough compared to theeffective dose.

[0216] Accordingly, the compounds and pharmaceutical compositions of thepresent invention are not only useful in the prevention and treatment ofarteriosclerosis caused by hyperlipidemia but also applicable toprevention and treatment of, for example, myocardial infarction,coronary artery diseases including reocclusion after percutaneoustransluminal coronary angioplasty (PTCA), angina pectoris and ischemicheart disease caused by coronary artery diseases, cerebral infarctionincluding cortical branch infarction and penetration branch infarction,thrombus and arteriosclerosis caused by the same, and the like.

[0217] Further, the compounds and pharmaceutical compositions of thepresent invention can be used in the prevention and treatment ofobesity, hypertension, diabetes mellitus, especially noninsulin-dependent diabetes mellitus.

[0218] When the compound of the invention is administered as a medicine,it can be administered to mammals inclusive of humans as it is or as apharmaceutical composition containing the compound in a pharmaceuticallyacceptable, nontoxic and inert carrier at a concentration of, forexample, 0.1% to 99.5%, preferably 0.5% to 90%.

[0219] Examples of usable carrier include solid, semisolid, or liquiddiluents, fillers, and other formulation auxiliaries, and at least oneof them is employed. The pharmaceutical composition is preferablyadministered in a unit dosage form. The pharmaceutical composition ofthe present invention can be administered intravenously, orally, intotissues, locally (e.g. transdermally) or rectally. A dosage form suitedfor each administration method is of course employed. The oraladministration is especially preferred.

[0220] The dosage of the pharmaceutical composition for prevention ortreatment of arteriosclerosis should preferably be adjusted inconsideration of conditions of the patient such as age, body weight; theroute of administration, nature and severity of disease; but the dailydosage of the compound of present invention as an active ingredient foradult can generally be 0.1-100 mg/human, preferably 0.5-20 mg/human. Thedose range above is not critical and a lower dosage under the said rangemay be sufficient in some cases, while a higher dosage over the saidrange may be needed in other cases. The daily dosage may be administeredin 2-to 3 divisions.

[0221] When the pharmaceutical composition is to be used in theprevention or treatment of diabetes mellitus or other diseases, the doseof the present compound can be adjusted in accordance with those setforth above.

BEST MODE FOR CARRYING OUT THE INVENTION

[0222] The following Examples including Reference Examples, WorkingExamples, Test Examples and Formulation Examples are provided to furtherillustrate the present invention in more detail, which should not beconstrued as limiting the scope of the present invention.

REFERENCE EXAMPLE 1 Diethyl (4-chlorobutyl)malonate

[0223] To 458 ml of dry tetrahydrofuran (THF) was added 13.4 g of 60%sodium hydride, and 160.6 g of diethyl malonate was added dropwise withstirring under ice-cooling. After addition, stirring was continued for15 minutes, and 57.3 g of 1-bromo-4-chlorobutane was added. The mixturewas stirred for 50 hours at room temperature. The reaction solution waspoured into ice-cold water, neutralized with dilute hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was distilled under reduced pressure to provide 26.8 g of theobjective compound as colorless oil. B.p. 127-130° C. (5 mmHg).

[0224] The following compounds were prepared by the same procedure asdescribed in Reference Example 1.

[0225] Diethyl (3-chloropropyl)malonate; and

[0226] Diethyl (5-chloropentyl)malonate.

REFERENCE EXAMPLE 2 Diethyl (5-hexenyl)malonate

[0227] To 120 ml of dry tetrahydrofuran (THF) was added 4.9 g of 60%sodium hydride, and 29.5 g of diethyl malonate was added dropwise withstirring under ice-cooling. After addition, stirring was continued for15 minutes, and then 10 g of 6-bromo-1-hexen was added to the mixtureand heated to reflux for 21 hours. The reaction solution was cooled,poured into ice-cold water, neutralized with dilute hydrochloric acidand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=20:1) to provide 14.5 g of the objectivecompound as yellowish oil.

[0228]¹H-NMR (CDCl₃)δ: 1.23-1.47 (10H, m), 1.84-2.11 (4H, m), 3.28-3.37(1H, m), 4.14-4.25 (4H, m), 4.91-5.05 (2H, m), 5.69-5.90 (1H, m).

REFERENCE EXAMPLE 3 6-Chloro-2-hydroxymethyl-1-hexanol

[0229] To 214 ml of dry ether was added 8 g of lithium aluminiumhydride, and a solution of 26.7 g of diethyl (4-chlorobutyl)malonate/53ml of dry ether was added dropwise with stirring under ice-cooling.After 1-hour-stirring at room temperature, the mixture was cooled withice-cold water, and 173 ml of tetrahydrofuran/14.7 ml of water was addedgradually. Then, 14.7 ml of 1N sodium hydroxide solution and 35 ml ofwater were added, stirred for 15 minutes, filtrated to removeinsolubles. The filtrate was concentrated to provide 18.2 g of theobjective compound as colorless oil.

[0230]¹H-NMR (CDCl₃)δ: 1.22-1.38 (2H, m), 1.42-1.58 (2H, m), 1.68-1.88(3H, m), 2.36-2.44 (2H, m), 3.55 (2H, t), 3.61-3.72 (2H, m), 3.77-3.88(2H, m).

[0231] The following compounds were prepared by the same procedure asdescribed in Reference Example 3.

[0232] 5-Chloro-2-hydroxymethyl-1-pentanol;

[0233] 7-Chloro-2-hydroxymethyl-1-heptanol; and

[0234] 2-Hydroxymethyl-7-octen-1-ol.

REFERENCE EXAMPLE 4 Methylc-5-(4-chlorobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate

[0235] To 270 ml of acetonitrile were added 18 g of6-chloro-2-hydroxymethyl-1-hexanol and 44 g of methyl pyruvate. To themixture solution, 65.2 g of boron trifluoride etherate (about 47%) wasadded with stirring at room temperature, and stirred for 14 hours. Thereaction mixture was poured into a solution of sodium bicarbonate inice-cold water and extracted with ethyl acetate. The organic layer waswashed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide14.8 g of the objective compound as yellowish oil.

[0236]¹H-NMR (CDCl₃)δ: 0.99-1.11 (2H, m), 1.37-1.55 (5H, m), 1.68-1.82(2H, m), 1.95-2.09 (1H, m), 3.41 (2H, t), 3.48-3.60 (2H, m), 3.83 (3H,s), 3.92-4.00 (2H, m).

[0237] The following compounds were prepared by the same procedure asdescribed in Reference Example 4.

[0238] Methyl c-5-(3-chloropropyl)-2-methyl-1,3-dioxane-r-2-carboxylate;and

[0239] Methyl c-5-(5-chloropentyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 5 Diethyl[4-(tetrahydro-2H-pyran-2-yloxy)-(Z)-2-butenyl]malonate

[0240] 2-[4-Chloro-(Z)-2-butenyloxy]tetrahydro-2H-pyran (100 g) wasdissolved in 2000 ml of dry tetrahydrofuran/600 ml of dryN,N-dimethylformamide. To the solution was added 100 g of diethylmalonate, and then 25 g of 60% sodium hydride with stirring underice-cooling, and the mixture was stirred at room temperature for 1 hour.The reaction mixture was poured into ice-cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=9:1) to provide 65.5 g of the objective compound as oil.

[0241]¹H-NMR (CDCl₃)δ: 1.27 (6H, t), 1.50-1.90 (6H, m), 2.67 (2H, t),3.39 (1H, t), 3.45-3.60 (1H, m), 3.80-3.95 (1H, m), 4.05-4.35 (6H, m),4.61 (1H, dd), 5.45-5.75 (2H, m).

REFERENCE EXAMPLE 62-Hydroxymethyl-6-(tetrahydro-2H-pyran-2-yloxy)-(Z)-4-hexen-1-ol

[0242] Diethyl [4-(tetrahydro-2H-pyran-2-yloxy)-(Z)-2-butenyl]malonate(65.5 g) was dissolved in 650 ml of dry tetrahydrofuran, and 15.1 g ofsodium borohydride was added thereto. A solution of 110 g ofmethanol/275 ml of tetrahydrofuran was added dropwise gradually withstirring under heating to reflux. Then, 13.18 g of lithium chloride and11 g of sodium borohydride were added and refluxed for 1.5 hours. Thereaction solution was cooled and poured into ice-cold water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (Wakogel® C-200,chloroform) to provide 22.8 g of the objective compound as oil.

[0243]¹H-NMR (CDCl₃)δ: 1.40-1.90 (7H, m), 2.20 (2H, br), 2.26 (2H, ddd),3.46-3.90 (6H, m), 4.10-4.30 (2H, m), 4.68 (1H, dd), 5.50-5.80 (2H, m).

REFERENCE EXAMPLE 7 Methylc-5-[4-hydroxy-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0244] Boron trifluoride etherate (about 47%, 26.8 g) was added dropwiseto a solution of 21.79 g of2-hydroxymethyl-6-(tetrahydro-2H-pyran-2-yloxy)-(Z)-4-hexen-1-ol, 430 mlof acetonitrile and 38.57 g of methyl pyruvate under ice-cooling, andthe mixture was stirred for 15 hours at room temperature. The reactionsolution was poured into a solution of sodium bicarbonate in ice-coldwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=7:1) to provide 5.36 g of the objectivecompound as oil.

[0245]¹H-NMR (CDCl₃)δ: 1.51 (3H, s), 1.85 (2H, dd), 1.95-2.20 (1H, m),3.43 (2H, dd), 3.84 (3H, s), 3.95 (2H, dd), 4.14 (2H, dd), 5.44 (1H,ddd), 5.70 (1H, ddd).

REFERENCE EXAMPLE 8 Methylc-5-[4-chloro-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0246] Methylc-5-[4-hydroxy-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate (538mg) was dissolved in 12 ml of N,N-dimethyl formamide, and 1.13 g of2,4,6-trimethylpyridine and 396 mg of lithium chloride were added. After1.07 g of methanesulfonyl chloride was added dropwise under ice-cooling,the mixture was stirred for 9 hours at room temperature. The reactionsolution was poured into ice-cold water, 0.5 N hydrochloric acid wasadded thereto and the solution was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide561 mg of the objective compound as oil.

[0247]¹H-NMR (CDCl₃)δ: 1.52 (3H, s), 1.89 (2H, dd), 2.00-2.20 (1H, m),3.45 (2H, dd), 3.85 (3H, s), 3.95 (2H, dd), 4.00 (2H, dd), 5.53 (1H,ddd), 5.72 (1H, ddd).

REFERENCE EXAMPLE 9 Methylc-5-[4-iodo-(E)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0248] Methylc-5-[4-chloro-(Z)-2-butenyl]-2-methyl-1,3-dioxane-r-2-carboxylate (300mg) was dissolved in 5 ml of acetone, and sodium iodide was addedthereto. The mixture was heated to reflux for 2 hours. The reactionsolution was cooled, ice-cold water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated toprovide 353 mg of the objective compound as oil.

[0249]¹H-NMR (CDCl₃)δ: 1.51 (3H, s), 1.79 (2H, dd), 2.00-2.20 (1H, m),3.41 (2H, dd), 3.81 (2H, dd), 3.84 (3H, t), 3.93 (2H, dd), 5.48-5.93(2H, m).

REFERENCE EXAMPLE 10 Methylc-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate

[0250] Methyl c-5-(4-chlorobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate(14.8 g) was dissolved in 148 ml of acetone, and 44.2 g of sodium iodidewas added. The mixture was stirred for 22.5 hours at 40° C. The reactionsolution was concentrated, water was added to the residue, and thesolution was extracted with ethyl acetate. The organic layer was washedwith brine, dried over anhydrous magnesium sulfate and concentrated togive 19.9 g of the objective compound as oil.

[0251]¹H-NMR (CDCl₃)δ: 0.99-1.10 (2H, m), 1.30-1.45 (2H, m), 1.51 (3H,s), 1.72-1.86 (2H, m), 1.97-2.08 (1H, m), 3.16 (2H, t), 3.40 (2H, t),3.83 (3H, s), 3.92-4.00 (2H, m).

[0252] The following compounds were prepared by the same procedure asdescribed in Reference Example 10.

[0253] Methyl c-5-(3-iodopropyl)-2-methyl-1,3-dioxane-r-2-carboxylate,and

[0254] Methyl c-5-(5-iodopentyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 11 6-Bromo-1-(tetrahydro-2H-pyran-2-yloxy)-2-hexyne

[0255] Under argon flow, 13.46 g of3-(tetrahydro-2H-pyran-2-yloxy)-1-propyne was dissolved in 135 ml ofanhydrous tetrahydrofuran, and 60 ml of 1.6 N n-butyllithium hexanesolution was added dropwise over 20 minutes with stirring at −10° C. ofinner temperature. The mixture was stirred for 1 hour at the sametemperature. After stirring for additional 1 hour at room temperature,the inner temperature was changed to −3° C., and 16.7 ml ofhexamethylphosphoric triamide (HMPA) was added to the mixture. Then58.14 g of 1,3-dibromopropane was added in a portion at −10° C. of innertemperature, and the mixture was stirred for 12 hours at roomtemperature. The reaction solution was poured into ice-cold water,extracted with ether, washed with water, dried over anhydrous magnesiumsulfate and concentrated. The residue was distilled under reducedpressure to give 12.0 g of the objective compound as colorless oil.

[0256] B.p. 121-126° C. (5 mmHg).

REFERENCE EXAMPLE 12 Methyl 2-(6-bromohexyloxy)-2-methylpropionate

[0257] To 120 ml of dry N,N-dimethylformamide, 4.0 g of 60% sodiumhydride was added. To the mixture was added dropwise 11.81 g of methyl2-hydroxyisobutyrate with stirring under ice-cooling, and stirred for 10minutes. Then, 122 g of 1,6-dibromohexane was added and stirred for 15hours at room temperature. The reaction solution was poured intoice-cold water, extracted with ethyl acetate, washed with brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=20:1) to provide 6.25 g of the objective compoundas yellowish oil.

[0258]¹H-NMR (CDCl₃)δ: 1.42-1.65 (12H, m), 1.80-1.94 (2H, m), 3.32-3.45(4H, m), 3.73 (3H, s).

[0259] The following compounds were prepared by the same procedure asdescribed in Reference Example 12.

[0260] Methyl 2-(5-bromopentyloxy)-2-methylpropionate,

[0261] Methyl 2-(7-bromoheptyloxy)-2-methylpropionate,

[0262] Methyl 2-(8-bromooctyloxy)-2-methylpropionate,

[0263] Ethyl2-methyl-2-[6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynyloxy]propionate,

[0264] Ethyl 2-(6-bromohexyloxy)-2-methylpropionate, and

[0265] Methyl2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenyloxy]-2-methylpropionate.

REFERENCE EXAMPLE 13 Ethyl 2-(6-hydroxy-4-hexynyloxy)-2-methylpropionate

[0266] Ethyl2-methyl-2-[6-(tetrahydro-2H-pyran-2-yloxy)-4-hexynyloxy]propionate(3.72 g) was dissolved in 37 ml of ethanol, and 15.372 mg of Amberlyst®was added thereto and the mixture was stirred for 1 hour at 55-60° C.After cooling, the mixture was filtrated and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1-3:1) toprovide 1.98 g of the objective compound as pale yellow oil.

[0267]¹H-NMR (CDCl₃)δ: 1.29 (3H, t), 1.42 (6H, s), 1.70-1.83 (2H, m),2.30-2.39 (2H, m), 3.44-3.50 (2H, m), 4.14-4.26 (4H, m).

REFERENCE EXAMPLE 14 Methyl 2-methyl-2-(8-nonenyloxy)propionate

[0268] To 500 ml of dry N,N-dimethylformamide, 17 g of 60% sodiumhydride was added, and 48 g of methyl 2-hydroxyisobutyrate was addeddropwise with stirring under ice-cooling, and stirred for 10 minutes.Then, 100 g of 9-bromo-1-nonene (purity: 63.4%) was added, and themixture was stirred for 15 hours at room temperature. The reactionsolution was poured into ice-cold water, extracted with ethyl acetate,washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was distilled under reduced pressure to give29.9 g of the objective compound as yellowish oil.

[0269] B.p. 124-127° C. (8 mmHg).

[0270] The following compounds were prepared by the same procedure asdescribed in Reference Example 14.

[0271] Methyl 2-(6-heptenyloxy)-2-methylpropionate,

[0272] Methyl 2-methyl-2-(7-octenyloxy)propionate and

[0273] Methyl 2-(9-decenyloxy)-2-methylpropionate.

REFERENCE EXAMPLE 15 Methyl 2-(8,9-epoxynonyloxy)-2-methylpropionate

[0274] Methyl 2-methyl-2-(8-nonenyloxy)propionate (40 g) was dissolvedin 320 ml of methylene chloride, and 40.8 g of 70% 3-chloroperbenzoicacid was added with stirring under ice-cooling, and the mixture wasstirred for 15 hours at room temperature. The reaction solution wasfiltrated to remove insolubles, and the filtrate was concentrated. Theresidue was dissolved in n-hexane and washed 4 times with aqueous 10%potassium carbonate solution, washed with water, dried over anhydrousmagnesium sulfate and concentrated to give 43.2 g of the objectivecompound as colorless oil.

[0275]¹H-NMR (CDCl₃)δ: 1.25-1.70 (18H, m), 2.44-2.48 (1H, m), 2.72-2.77(1H, m), 2.85-2.97 (1H, m), 3.34 (2H, t), 3,73 (3H, s).

[0276] The following compounds were prepared by the same procedure asdescribed in Reference Example 15.

[0277] Methyl 2-(6,7-epoxyheptyloxy)-2-methylpropionate,

[0278] Methyl 2-(7,8-epoxyoctyloxy)-2-methylpropionate,

[0279] Methyl 2-(9,10-epoxydecyloxy)-2-methylpropionate and

[0280] Methyl c-5-(5,6-epoxyhexyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 16 Methyl2-(9-chloro-8-hydroxynonyloxy)-2-methylpropionate

[0281] Methyl 2-(8,9-epoxynonyloxy)-2-methylpropionate (26 g) wasdissolved in 260 ml of dry tetrahydrofuran, and 6.8 g of lithiumchloride and 7 g of acetic acid were added and the mixture was stirredfor 22 hours at room temperature. The reaction solution was poured intoice-cold water, extracted with ethyl acetate, washed with saturatedsodium hydrogen carbonate solution and brine, dried over anhydrousmagnesium sulfate and concentrated to give 31.7 g of the objectivecompound as oil.

[0282] The following compounds were prepared by the same procedure asdescribed in Reference Example 16.

[0283] Methyl 2-(7-chloro-6-hydroxyheptyloxy)-2-methyl-propionate,

[0284] Methyl 2-(8-chloro-7-hydroxyoctyloxy)-2-methyl-propionate,

[0285] Methyl 2-(10-chloro-9-hydroxydecyloxy)-2-methyl-propionate and

[0286] Methylc-5-(6-chloro-5-hydroxyhexyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 17 Methyl2-(9-chloro-8-oxononyloxy)-2-methylpropionate

[0287] Methyl 2-(9-chloro-8-hydroxynonyloxy)-2-methylpropionate (31 g)was dissolved in 465 ml of acetone, and 46 ml of Jones reagent preparedby adding 10.2 ml of conc. sulfuric acid and 12 g of chromic (VI) oxideto 45 ml of water was added dropwise with stirring under ice-cooling.After 3-hour-stirring at room temperature, an excess amount of Jonesreagent was decomposed by adding isopropyl alcohol, The reaction mixturewas poured into ice-cold water, extracted with ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=7.5:1) to provide 18.16 g of the objectivecompound as oil.

[0288]¹H-NMR (CDCl₃)δ: 1.24-1.40 (6H, m), 1.41 (6H, s), 1.45-1.75 (4H,m), 2.58 (2H, t), 3.34 (2H, t), 3.73 (3H, s), 4.07 (2H, s).

[0289] The following compounds were prepared by the same procedure asdescribed in Reference Example 17.

[0290] Methyl 2-(7-chloro-6-oxoheptyloxy)-2-methylpropionate,

[0291] Methyl 2-(8-chloro-7-oxooctyloxy)-2-methylpropionate,

[0292] Methyl 2-(10-chloro-9-oxodecyloxy)-2-methylpropionate and

[0293] Methylc-5-(6-chloro-5-oxohexyl)-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 18 Diethyl p-toluoylaminomalonate

[0294] Diethyl aminomalonate hydrochloride (20.5 g) was suspended into180 ml of methylene chloride, and 29.4 g of triethylamine was addedwhile cooling with ice-cold water. After 30-minute-stirring, 15 g ofp-toluoyl chloride was added dropwise, and the mixture was stirred for24 hours at room temperature. The reaction solution was washed withwater, dilute hydrochloric acid, and water, dried over anhydrousmagnesium sulfate and concentrated. To the residue was added isopropylether, and the resultant crystals were collected by filtration and driedto provide 25.9 g of the objective compound as white crystal. M.p.101-102° C.

[0295] The following compounds were prepared by the same procedure asdescribed in Reference Example 18.

[0296] Diethyl benzoylaminomalonate,

[0297] Diethyl (4-chlorobenzoyl)aminomalonate,

[0298] Diethyl (4-fluorobenzoylamino)malonate,

[0299] Diethyl (4-trifluoromethylbenzoyl)aminomalonate,

[0300] Diethyl (4-tert-butylbenzoyl)aminomalonate and

[0301] Diethyl (4-ethylbenzoyl)aminomalonate.

REFERENCE EXAMPLE 19 Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(p-toluoylamino)-pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0302] To 27 ml of dry ethanol, 6.6 g of 20% sodium ethoxide-ethanolsolution and 5.4 g of diethyl p-toluoylaminomalonate were added, andstirred for 30 minutes at room temperature. Then, a solution of 6.3 g ofmethyl c-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate/5.4 ml ofdry ethanol was added dropwise and stirred for 15 hours at 50-60° C. Thereaction solution was poured into ice-cold water and extracted withethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=5:1) to provide 4.34 g of the objective compound as yellowishcrystals. M.p. 60-63° C.

[0303] The following compounds were prepared by the same procedure asdescribed in Reference Example 19.

[0304] Ethylc-5-(4-benzoylamino-4,4-bis(ethoxycarbonyl)-butyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0305] Ethylc-5-(5-benzoylamino-5,5-bis(ethoxycarbonyl)-pentyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0306] Ethylc-5-(6-benzoylamino-6,6-bis(ethoxycarbonyl)-hexyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0307] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(4-fluoro-benzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0308] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(4-trifluoro-methylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0309] Ethylc-5-[5-(4-tert-butylbenzoylamino)-5,5-bis-(ethoxycarbonyl)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0310] Ethylc-5-[5-benzoylamino-5,5-bis(ethoxycarbonyl)-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0311]5-(5-Benzolyamino-5,5-bis(ethoxycarbonyl)pentyl-2,2-dimethyl-1,3-dioxane,

[0312] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(4-chlorobenzoyl-amino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0313] Ethylc-5-[6,6-bis(ethoxycarbonyl)-6-(p-toluoylamino)-hexyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0314] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(3-fluoro-4-methylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylateand

[0315] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(4-ethylbenzoyl-amino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 20 Ethyl2-(7-benzoylamino-7,7-bis(ethoxycarbonyl)-heptyloxy)-2-methylpropionate

[0316] To 5 ml of dry ethanol, 675 mg of 20% sodium ethoxide-ethanolsolution and 698 mg of diethyl benzoylaminomalonate were added, andstirred for 30 minutes at room temperature. Then, a solution of 914 mgof methyl 6-bromohexyloxy-2-methylpropionate/4 ml of dry ethanol wasadded dropwise, and stirred for 15 hours at 50-60° C. The reactionsolution was poured into ice-cold water and extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=5:1)to provide 642 mg of the objective compound as yellowish oil.

[0317]¹H-NMR (CDCl₃) δ: 1.10-1.37 (15H, m), 1.38 (6H, s), 1.42-1.60 (2H,m), 2.41-2.49 (2H, m), 3.30 (2H, t), 4.11-4.33 (6H, m), 7.40-7.60 (4H,m), 7.81-7.86 (2H, m).

[0318] The following compounds were prepared by the same procedure asdescribed in Reference Example 20.

[0319] Ethyl2-methyl-2-[7-(p-toluoylamino)-7,7-bis(ethoxycarbonyl)heptyloxy]propionate,

[0320] Ethyl2-[7-benzoylamino-7,7-bis(ethoxycarbonyl)-4-heptynyloxy]-2-methylpropionate,

[0321] Ethyl2-[7-(4-chlorobenzoylamino)-7,7-bis(ethoxy-carbonyl)heptyloxy]-2-methylpropionate,

[0322] Ethyl2-7,7-bis(ethoxycarbonyl)-7-(4-fluorobenzoyl-amino)heptyloxy]-2-methylpropionate,

[0323] Ethyl2-[7-(4-tert-butylbenzoylamino)-7,7-bis(ethoxycarbonyl)heptyloxy]-2-methylpropionate,

[0324] Ethyl2-[6-benzoylamino-6,6-bis(ethoxycarbonyl)hexyloxy]-2-methylpropionate,

[0325] Ethyl2-[8-benzoylamino-8,8-bis(ethoxycarbonyl)octyloxy]-2-methylpropionate,

[0326] Ethyl 5-benzoylamino-5,5-bis(ethoxycarbonyl)pentanoate,

[0327] Ethyl 6-benzoylamino-6,6-bis(ethoxycarbonyl)hexanoate,

[0328] Ethyl 5,5-bis(ethoxycarbonyl)-5-(p-toluoylamino)pentanoate and

[0329] 5-(Benzoylamino)-1-bromo-5,5-bis(ethoxycarbonyl)-(E)-2-pentene.

REFERENCE EXAMPLE 21c-5-[5-Carboxy-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid

[0330] Ethylc-5-[5,5-bis(ethoxycarbonyl)-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate(4.2 g) was dissolved in 33.6 ml of ethanol, and a solution of 2.0 g ofsodium hydroxide/8.4 ml of water was added. The mixture was heated toreflux for 5 hours. The reaction solution was concentrated. Water wasadded to the residue, and the mixture was acidified with hydrochloricacid and extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated toprovide 3.23 g of yellowish oil. The resultant oil was stirred for 30minutes at 130° C. to give 3.1 g of the objective compound as whitecrystals. M.p. 152-156° C.

[0331] The following compounds were prepared by the same procedure asdescribed in Reference Example 21.

[0332]c-5-(4-Benzoylamino-4-carboxybutyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0333]c-5-(5-Benzoylamino-5-carboxypentyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0334]c-5-(6-Benzoylamino-6-carboxyhexyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0335]c-5-[5-Carboxy-5-(4-fluorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0336]c-5-[5-Carboxy-5-(4-trifluoromethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0337]c-5-[5-(4-tert-Butylbenzoylamino)-5-carboxypentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0338]c-5-[5-Benzoylamino-5-carboxy-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0339] 5-(5-Benzoylamino-5-carboxypentyl)-2,2-dimethyl-1,3-dioxane,

[0340] 2-(7-Benzoylamino-7-carboxyheptyloxy)-2-methylpropionic acid,

[0341] 2-[7-Carboxy-7-(p-toluoylamino)heptyloxy]-2-methylpropionic acid,

[0342] 2-(⁷-Benzoylamino-7-carboxy-4-heptynyloxy)-2-methylpropionicacid,

[0343] 2-[7-Carboxy-7-(4-chlorobenzoylamino)heptyloxy]-2-methylpropionicacid,

[0344] 2-[7-Carboxy-7-(4-fluorobenzoylamino)heptyloxy]-2-methylpropionicacid,

[0345]2-[7-(4-tert-Butylbenzoylamino)-7-carboxyheptyloxy)-2-methylpropionicacid,

[0346] 2-(8-Benzoylamino-8-carboxyoctyloxy)-2-methylpropionic acid,

[0347] 2-(6-Benzoylamino-6-carboxyhexyloxy)-2-methylpropionic acid,

[0348] 5-Benzoylamino-5-carboxypentanoic acid,

[0349] 6-Benzoylamino-6-carboxyhexanoic acid;

[0350]c-5-[5-Carboxy-5-(4-chlorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0351]c-5-[6-Carboxy-6-(p-toluoylamino)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0352] 5-Carboxy-5-(p-toluoylamino)pentanoic acid,

[0353]c-5-[5-Carboxy-5-(3-fluoro-4-methylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid and

[0354]c-5-[5-Carboxy-5-(4-ethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid.

REFERENCE EXAMPLE 22c-5-[5-Acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid

[0355]c-5-[5-Carboxy-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid (3.1 g) was dissolved in 15.5 ml of pyridine, and 10.2 ml of aceticanhydride was added and stirred for 1 hour at 90° C. Then, 10.2 ml ofwater was added dropwise and stirred for 30 minutes at 90° C. Thereaction solution was cooled, poured into ice-cold water, extracted withethyl acetate, washed with brine, dried over anhydrous magnesium sulfateand concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, chloroform:methanol=100:1) to provide2.2 g of the objective compound as yellowish oil.

[0356]¹H-NMR (CDCl₃)δ: 0.99-1.10 (2H, m), 1.15-1.45 (4H, m), 1.54 (3H,s), 1.50-1.82 (1H, m), 1.84-2.15 (2H, m), 2.27 (3H, s), 2.40 (3H, s),3.47 (2H, dd), 3.89-4.04 (2H, m), 4.82-4.92 (1H, m), 7.01 (1H, d),7.22-7.27 (2H, m), 7.68-7.74 (2H, m).

[0357] The following compounds were prepared by the same procedure asdescribed in Reference Example 22.

[0358]c-5-(4-Acetyl4-benzoylaminobutyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0359]c-5-(5-Acetyl-5-benzoylaminopentyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0360]c-5-(6-Acaetyl-6-benzoylaminohexyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0361]c-5-[5-Acetyl-5-(4-fluorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0362]c-5-[5-Acetyl-5-(4-trifluoromethylbenzoylamino)-pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0363]c-5-[5-Acetyl-5-(4-tert-butylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0364]c-5-[5-Acetyl-5-benzoylamino-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0365] 5-(5-Acetyl-5-benzoylaminopentyl)-2,2-dimethyl-1,3-dioxane,

[0366] 2-(7-Acetyl-7-benzoylaminoheptyloxy)-2-methylpropionic acid,

[0367] 2-[7-Acetyl-7-(p-toluoylamino)heptyloxy]-2-methylpropionic acid,

[0368] 2-(7-Acetyl-7-benzoylamino-4-heptynyloxy)-2-methylpropionic acid,

[0369] 2-[7-Acetyl-7-(4-chlorobenzoylamino)heptyloxy]-2-methylpropionicacid,

[0370] 2-[7-Acetyl-7-(4-fluorobenzoylamino)heptyloxy]-2-methylpropionicacid,

[0371]2-[7-Acetyl-7-(4-tert-butylbenzoylamino)heptyloxy)-2-methylpropionicacid,

[0372] 2-(8-Acetyl-8-benzoylaminooctyloxy)-2-methylpropionic acid,

[0373] 2-(6-Acetyl-6-benzoylaminohexyloxy)-2-methylpropionic acid,

[0374] 5-Acetyl-5-benzoylaminopentanoic acid,

[0375] 6-Acetyl-6-benzoylaminohexanoic acid,

[0376]c-5-[5-Acetyl-5-(4-chlorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0377]c-5-[6-Acetyl-6-(p-toluoylamino)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0378] 5-Acetyl-5-(p-toluoylamino)pentanoic acid,

[0379]c-5-[5-Acetyl-5-(3-fluoro-4-methylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid,

[0380]c-5-[5-Acetyl-5-(4-ethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid and

[0381] 7-Acetyl-7-(benzoylamino)-(E)-4-heptenoic acid.

REFERENCE EXAMPLE 23 Methylc-5-[5-Acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0382]c-5-[5-Acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid (2.1 g) was dissolved in 44 ml of benzene and 4.2 ml of methanol,and 4.2 ml of 2.0 M trimethylsilyldiazomethane/hexane solution was addeddropwise with stirring under ice-cooling. The mixture was stirred for 1hour, and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=2.5:1) to provide0.85 g of the objective compound as yellowish oil.

[0383]¹H-NMR (CDCl₃)δ: 0.90-1.08 (2H, m), 1.10-1.40 (4H, m), 1.50 (3H,s), 1.55-1.80 (1H, m), 1.85-2.16 (2H, m), 2.27 (3H, s), 2.40 (3H, s),3.36 (2H, dd), 3.82 (3H, s), 3.92 (2H, dd), 4.80-4.89 (1H, m), 6.89 (1H,d), 7.25 (2H, d), 7.70 (2H, d).

[0384] The following compounds were prepared by the same procedure asdescribed in Reference Example 23.

[0385] Methylc-5-(4-acetyl-4-benzoylaminobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0386] Methylc-5-(5-acetyl-5-benzoylaminopentyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0387] Methylc-5-(6-acetyl-6-benzoylaminohexyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0388] Methylc-5-[5-acetyl-5-(4-fluorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0389] Methylc-5-[5-acetyl-5-(4-trifluoromethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0390] Methylc-5-[5-acetyl-5-(4-tert-butylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylateand

[0391] Methylc-5-[5-acetyl-5-benzoylamino-(E)-2-pentenyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 24 Methylc-5-[5-acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0392]c-5-[5-Acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylicacid (20 g) was dissolved in 140 ml of acetonitrile, and 14.5 g ofmethyl iodide and 14.1 g of potassium carbonate were added. The mixturewas heated to reflux for 3 hours. The reaction solution was cooled,poured into ice-cold water, extracted with ethyl acetate, washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=2:1) to provide 10.3 g of the objectivecompound as yellowish oil.

[0393] The following compounds were prepared by the same procedure asdescribed in Reference Example 24.

[0394] Methylc-5-(5-acetyl-5-benzoylaminopentyl)-2-methyl-1,3-dioxane-r-2-carboxylate,

[0395] Methylc-5-[5-acetyl-5-(4-chlorobenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0396] Methylc-5-[6-acetyl-6-(p-toluoylamino)hexyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0397] Methylc-5-[5-acetyl-5-(3-fluoro-4-methylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylateand

[0398] Methylc-5-[5-acetyl-5-(4-ethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 25 Methyl 6-acetyl-6-benzoylaminohexanoate

[0399] 6-Acetyl-6-benzoylaminohexanoic acid (4.35 g) was dissolved in100 ml of methanol, and 0.5 ml of conc. sulfuric acid was added. Themixture was heated to reflux for 2.5 hours. The reaction solution wascooled, poured into ice-cold water, extracted with ethyl acetate, washedwith brine, dried over anhydrous magnesium sulfate and concentrated toprovide 4.4 g of the objective compound as yellowish crystals. M.p.59-60° C.

[0400] The following compounds were prepared by the same procedure asdescribed in Reference Example 25.

[0401] Methyl 2-(7-acetyl-7-benzoylaminoheptyloxy)-2-methylpropionate,

[0402] Methyl2-[7-acetyl-7-(p-toluoylamino)heptyloxy]-2-methyl-propionate,

[0403] Methyl2-(7-acetyl-7-benzoylamino-4-heptynyloxy)-2-methylpropionate,

[0404] Methyl2-[7-acetyl-7-(4-chlorobenzoylamino)heptyloxy]-2-methylpropionate,

[0405] Methyl2-[7-acetyl-7-(4-fluorobenzoylamino)heptyloxy]-2-methylpropionate,

[0406] Methyl2-[7-acetyl-7-(4-tert-butylbenzoylamino)heptyloxy]-2-methylpropionate,

[0407] Methyl 2-(8-acetyl-8-benzoylaminooctyloxy)-2-methylpropionate,

[0408] Methyl 2-(6-acetyl-6-benzoylaminohexyloxy)-2-methylpropionate,

[0409] Methyl 5-acetyl-5-benzoylaminopentanoate

[0410] Methyl 5-acetyl-5-(p-toluoylamino)pentanoate and

[0411] Methyl 7-acetyl-7-(benzoylamino)-(E)-4-heptenoate.

REFERENCE EXAMPLE 26 Diethyl (3-bromobenzyl)malonate

[0412] Sodium hydride (60%, 1.6 g) was suspended into 20 ml of drytetrahydrofuran/15 ml of dry N,N-dimethyl formamide, and 7.6 ml ofdiethyl malonate was added dropwise under ice-cooling. The mixture wasstirred for 15 minutes. A solution of 5 g of 3-bromobenzyl bromide/10 mlof dry tetrahydrofuran was then added, and stirred for 1 hour underice-cooling. To the reaction solution was added ice-cold water, andextracted with ether, washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide5.41 g of the objective compound as colorless oil.

[0413]¹H-NMR (CDCl₃)δ: 1.22 (6H, t), 3.81 (2H, d), 3.61 (1H, t), 4.17(4H, q), 7.10-7.20 (2H, m), 7.29-7.40 (2H, m).

[0414] The following compound was prepared by the same procedure asdescribed in Reference Example 26.

[0415] Diethyl (4-bromobenzyl)malonate.

REFERENCE EXAMPLE 27 Diethyl (4-bromphenyl)malonate

[0416] Under argon flow, 10.85 g of diethyl carbonate was dissolved in60 ml of benzene, and 2.75 g of 60% sodium hydride was added and themixture was heated to reflux. A solution of 5.58 g of ethyl4-bromophenylacetate/20 ml of benzene was added dropwise to the solutionover 1 hour, and the mixture was heated to reflux for 1 hour. Aftercooling, ice-cold water was added dropwise to the reaction solutionslowly. The organic layer was separated, washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=10:1) to provide 6.45 g of the objective compound as colorlessoil.

[0417]¹H-NMR (CDCl₃)δ: 1.26 (6H, t), 4.21 (4H, q), 4.56 (1H, s), 7.29(2H, d), 7.50 (2H, d).

[0418] The following compound was prepared by the same procedure asdescribed in Reference Example 27.

[0419] Diethyl (3-bromophenyl)malonate.

REFERENCE EXAMPLE 28 2-(3-Bromobenzyl)-1,3-propanediol

[0420] To an ice-cooled 94 ml of 1.0 M diisobutylalminium hydridetoluene solution was added dropwise 5.41 g of diethyl(3-bromobenzyl)malonate at 15° C. or less under argon flow. The mixturewas stirred for 30 minutes under ice-cooling, warmed to room temperatureand stirred for 2 hours. The reaction solution was ice-cooled, and 21 mlof methanol was added dropwise slowly, then 41 ml of 2 N hydrochloricacid was added dropwise. The mixture was stirred for 20 minutes at roomtemperature. The reaction solution was filtered to remove insolubles,extracted with ethyl acetate, washed with saturated sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, chloroform:methanol=10:1) to provide 1.96 g of the objectivecompound as white crystals. M.p. 61-63° C.

[0421] The following compounds were prepared by the same procedure asdescribed in Reference Example 28.

[0422] 2-(4-Bromobenzyl)-1,3-propanediol,

[0423] 2-(4-Bromophenyl)-1,3-propanediol and

[0424] 2-(3-Bromophenyl)-1,3-propanediol.

REFERENCE EXAMPLE 29 5-(3-Bromobenzyl)-2,2-dimethyl-1,3-dioxane

[0425] 2-(3-Bromobenzyl)-1,3-propanediol (1.85 g) was dissolved in amixture of 8 ml of acetone/18 ml of benzene, and 70 mg ofp-toluenesulfonic acid monohydrate was added. The solution was subjectedto azeotropic dehydration with Dean-Stark apparatus for 1 hour. Afteraddition of saturated sodium hydrogen carbonate solution, the mixturewas extracted with ethyl acetate, dried over anhydrous magnesium sulfateand concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide1.47 g of the objective compound as colorless oil.

[0426]¹H-NMR (CDCl₃)δ: 1.43 (6H, d), 1.90-2.10 (1H, m), 2.60 (2H, d),3.61 (2H, dd), 3.86 (2H, dd), 7.05-7.20 (2H, m), 7.30-7.40 (2H, m).

[0427] The following compounds were prepared by the same procedure asdescribed in Reference Example 29.

[0428] 5-(4-Bromobenzyl)-2,2-dimethyl-1,3-dioxane,

[0429] 5-(4-Bromophenyl)-2,2-dimethyl-1,3-dioxane and

[0430] 5-(3-Bromophenyl)-2,2-dimethyl-1,3-dioxane.

REFERENCE EXAMPLE 302,2-Dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane

[0431] Under argon flow, 1.45 g of5-(3-bromobenzyl)-2,2-dimethyl-1,3-dioxane was dissolved in 7 ml of drytetrahydrofuran, and cooled with the dry ice-acetone bath. To themixture was added 0.9 ml of N,N,N′,N′-tetramethylethylenediamine, andthen n-butyllithium (1.6 M hexane solution) was added dropwise at −60°C. or less. After 10-minute-stirring, a suspension of 1.03 g oftri-n-butylphosphine and 0.97 g of copper iodide/7 ml of drytetrahydrofuran was added and the mixture- was stirred for 10 minutes. Asolution of 1.52 g of 4-iodomethyl-5-methyl-2-phenyloxazole/7 ml of drytetrahydrofuran was added dropwise at −60° C. or less, and the mixturewas stirred for 15 minutes under the same conditions. The bath wasremoved and the mixture was stirred for 1.5 hours. To the reactionsolution was added saturated aqueous ammonium chloride solution. Themixture was diluted with water, extracted with ether, filtrated toremove insolubles, washed with water, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide0.34 g of the objective compound as white crystals. M.p. 85-87° C.

[0432] The following compounds were prepared by the same procedure asdescribed in Reference Example 30.

[0433]2,2-Dimethyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane,

[0434]2,2-Dimethyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxaneand

[0435]2,2-Dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane.

REFERENCE EXAMPLE 31 5-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol

[0436] To 17 ml of dry ether, 550 mg of lithium aluminum hydride wasadded and 3.3 g of methyl5-(5-methyl-2-phenyloxazol-4-yl)-1-pentanoate/10 ml of dry ether wasadded dropwise. After 1-hour-stirring at room temperature, the mixturewas cooled with ice-cold water and 12 ml of tetrahydrofuran/0.7 ml ofwater was added dropwise gradually. Then, 0.7 ml of 1N sodium hydroxideand 2.5 ml of water were added and stirred for 15 minutes. The mixturewas filtrated to remove insolubles and the filtrate was concentrated toprovide 2.9 g of the objective compound as yellowish crystals. M.p.40-42° C.

[0437] The following compounds were prepared by the same procedure asdescribed in Reference Example 31.

[0438] 4-(5-Methyl-2-phenyloxazol-4-yl)-1-butanol,

[0439] 4-[5-Methyl-2-(p-tolyl)oxazol-4-yl]-1-butanol,

[0440] 4-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]-1-butanol,

[0441] 6-[5-Methyl-2-(p-tolyl)oxazol-4-yl]-1-hexanol and

[0442] 6-(5-Methyl-2-phenyloxazol-4-yl)-(E)-4-hexen-1-ol.

REFERENCE EXAMPLE 32 4-(5-Bromopentyl)-5-methyl-2-phenyloxazole

[0443] 5-(5-Methyl-2-phenyloxazol-4-yl)-1-pentanol (2.9 g) was dissolvedin 62 ml of dry ether, and 8.4 g of carbon tetrabromide was added. Tothe mixture was added gradually 6.6 g of triphenylphosphine underice-cooling. The mixture was then stirred for 2.5 hours at roomtemperature, filtrated to remove insolubles and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide2.61 g of the objective compound as yellowish oil.

[0444] The following compounds were prepared by the same procedure asdescribed in Reference Example 32.

[0445] 4-(4-Bromobutyl)-5-methyl-2-phenyloxazole,

[0446] Ethyl 2-(6-bromo-4-hexynyloxy)-2-methylpropionate,

[0447] 4-(4-Bromobutyl)-5-methyl-2-(p-tolyl)oxazole,

[0448] 4-(4-Bromobutyl)-2-(p-tolyl)-5-trifluoromethyloxazole,

[0449] 4-(6-Bromohexyl)-5-methyl-2-(p-tolyl)oxazole and

[0450] 4-[6-Bromo-(E)-2-hexenyl]-5-methyl-2-phenyloxazole.

REFERENCE EXAMPLE 33 Diethyl[5-(5-methyl-2-phenyloxazol-4-yl)pentyl]-malonate

[0451] To 35 ml of dry tetrahydrofuran, 650 mg of 60% sodium hydride wasadded, and 3.9 g of diethyl malonate was added dropwise with stirringunder ice-cooling. After the stirring was continued for 10 minutes,4-(4-bromopentyl)-5-methyl-2-phenyloxazol (2.5 g) was added. The mixturewas stirred for 10 minutes at room temperature and then heated to refluxfor 12 hours. The reaction solution was poured into ice-cold water,neutralized with dilute hydrochloric acid and then extracted with ethylacetate. The organic layer was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1)to provide 2.75 g of the objective compound as colorless oil.

[0452]¹H-NMR (CDCl₃)δ: 1.26 (6H, t), 1.32-1.43 (4H, m), 1.55-1.75 (2H,m), 1.82-2.00 (2H, m), 2.31 (3H, s), 2.47 (2H, t), 3.31 (1H, t), 4.19(4H, q), 7.37-7.47 (3H, m), 7.95-8.00 (2H, m).

[0453] The following compounds were prepared by the same procedure asdescribed in Reference Example 33.

[0454] Diethyl [4-(5-Methyl-2-phenyloxazol-4-yl)butyl]malonate,

[0455] Diethyl {4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}malonate,

[0456] Diethyl{4-[2-(p-tolyl)-5-trifluoromethyloxazol-4-yl]butyl}malonate and

[0457] Diethyl[5-(benzoylamino)-5,5-bis(ethoxycarbonyl)-(E)-2-pentenyl]malonate.

REFERENCE EXAMPLE 344-[6,6-Bis(hydroxymethyl)hexyl]-5-methyl-2-phenyloxazole

[0458] To 15 ml of dry ether, 637 mg of lithium aluminium hydride wasadded, and 2.6 g of diethyl[5-(5-methyl-2-phenyloxazol-4-yl)pentyl]malonate/10 ml of dry ether wasadded dropwise. After 2-hour-stirring at room temperature, the mixturewas cooled with ice-cold water, and 14 ml of tetrahydrofuran/0.8 ml ofwater was added dropwise gradually. To the mixture were added 0.8 ml ofan aqueous solution of 1 N sodium hydroxide and 2.3 ml of water, andstirred for 15 minutes and filtrated to remove insolubles. The filtratewas concentrated to provide 2.0 g of the objective compound as whitecrystals. M.p. 71-74° C.

[0459] The following compounds were prepared by the same procedure asdescribed in Reference Example 34.

[0460] 4-[5,5-Bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazole,

[0461] 4-[5,5-Bis(hydroxymethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole,

[0462]4-[5,5-Bis(hydroxymethyl)pentyl]-2-(p-tolyl)-5-trifluoromethyloxazoleand

[0463] 4-[5,5-Bis(hydroxymethyl)pentyl]-5-ethyl-2-(p-tolyl)oxazole.

REFERENCE EXAMPLE 354-{3-[2,2-Bis(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole

[0464] A mixture solution of 320 mg of2,2-dimethyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane,21 ml of ethanol and 21 mg of pyridinium p-toluenesulfonate (PPTS) wasstirred for 2 hours at 55-60° C. The reaction solution was concentratedand the residue was purified by silica gel column chromatography(Wakogel® C-200, chloroform) to provide 305 mg of the objective compoundas colorless oil.

[0465]¹H-NMR (CDCl₃)δ: 1.90-2.15 (1H, m), 2.29 (3H, s), 2.35 (2H, br),2.60 (2H, d), 3.64 (2H, dd), 3.78 (2H, dd), 3.85 (2H, s), 6.90-7.50 (7H,m), 7.85-8.05 (2H, m).

[0466] The following compounds were prepared by the same procedure asdescribed in Reference Example 35.

[0467]4-{4-[2,2-Bis(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole,

[0468]4-{4-[1,1-Bis(hydroxymethyl)methyl]benzyl}-5-methyl-2-phenyloxazole,

[0469]4-{3-[1,1-Bis(hydroxymethyl)methyl]benzyl}-5-methyl-2-phenyloxazole and

[0470] 4-[5,5-Bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazole.

REFERENCE EXAMPLE 36 Methyl 5-(5-methyl-2-phenyloxazol-4-yl)pentanoate

[0471] Methyl 6-acetyl-6-benzoylaminohexanoate (4.35 g) was dissolved in87 ml of toluene, and 2.9 ml of phosphorus oxychloride was added andheated to reflux for 50 minutes. The reaction solution was cooled,poured into ice-cold water, neutralized with aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and washed with brine.The resulting solution was dried over anhydrous magnesium sulfate andconcentrated to provide 3.40 g of the objective compound as yellowishoil.

[0472] The following compounds were prepared by the same procedure asdescribed in Reference Example 36.

[0473] Methyl 4-(5-methyl-2-phenyloxazol-4-yl)butanoate,

[0474] Methyl 4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butanoate,

[0475] Ethyl 6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexanoate and

[0476] Methyl 6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenoate.

REFERENCE EXAMPLE 371-Bromo-3-[2,2-bis(ethoxycarbonyl)-2-(p-toluoylamino)ethyl]benzene

[0477] To 100 ml of dry ethanol, 21.45 g of 20% sodium ethoxide-ethanolsolution and 17.61 g of diethyl p-toluoylaminomalonate were added andstirred for 30 minutes at room temperature under argon atmosphere. After15.00 g of 3-bromobenzyl bromide was added dropwise, the reactionsolution was stirred for 8 hours at 55° C. and then concentrated. To theresidue was added water, and extracted with ethyl acetate. Theorganic.layer was washed with brine and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to provide29.82 g of the objective compound as yellow oil.

[0478]¹H-NMR (CDCl₃)δ: 1.31 (6H, t), 2.41 (3H, s), 3.74 (2H, s), 4.30(4H, q), 6.90-7.40 (7H, m), 7.60-7.70 (2H, m).

REFERENCE EXAMPLE 381-Bromo-3-[2-carboxy-2-(p-toluoylamino)ethyl]benzene

[0479]1-Bromo-3-[2,2-bis(ethoxycarbonyl)-2-(p-toluoylamino)ethyl]benzene(28.93 g) was dissolved in 200 ml of ethanol, and a solution of 9.6 g ofsodium hydroxide/60 ml of water was added and heated to reflux for 3hours. The reaction solution was concentrated. To the residue was addedwater, and washed with diethyl ether. The aqueous layer was acidifiedwith hydrochloric acid, extracted with ethyl acetate. The organic layerwas dried over anhydrous magnesium sulfate and concentrated to provide24.19 g of the objective compound as colorless oil. The resulting oilwas dissolved in 150 ml of ethyl acetate and, after addition of 150 mlof xylene, stirred for 15 hours at 130° C. The solvent was distilled offunder reduced pressure and the resulting crystals were washed withdiethyl ether to provide 17.22 g of the objective compound as colorlesscrystals. M.p. 196-197° C.

REFERENCE EXAMPLE 39 1-[2-Acetyl-2-(p-toluoylamino)ethyl]-3-bromobenzene

[0480] 1-Bromo-3-[2-carboxy-2-(p-toluoylamino)ethyl]benzene (16.84 g)was dissolved in 85 ml of pyridine, and 55 ml of acetic anhydride wasadded and stirred for 3 hours under argon atmosphere at 90-95° C. Water(55 ml) was added dropwise gradually so that the maximum temperature didnot exceed 100° C., and the mixture was stirred for 20 minutes at 60-70°C. The reaction solution was cooled, poured into ice-cold water andextracted with ethyl acetate. The resulting solution was washed with 10%hydrochloric acid, water and saturated aqueous sodium hydrogen carbonatesolution sequentially and dried over anhydrous magnesium sulfate. Thesolvent was distilled off under reduced pressure. The resulting crystalswere washed with isopropyl ether to provide 13.31 g of the objectivecompound as brownish crystals. M.p. 106-107 ° C.

REFERENCE EXAMPLE 401-Bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene

[0481] 1-[2-Acetyl-2-(p-toluoylamino) ethyl]-3-bromobenzene (13.26 g)was dissolved in 260 ml of toluene, and 6.8 ml of phosphorus oxychloridewas added and heated to reflux for 3 hours. The reaction solution wascooled, poured into ice-cold water and extracted with ethyl acetate. Theresulting solution was washed with aqueous solution of saturated sodiumhydrogen carbonate, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide10.86 g of the objective compound as yellowish crystals. M.p. 74-75° C.

REFERENCE EXAMPLE 413-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzaldehyde

[0482] N,N-Dimethylformamide (30 ml) was added to 9.48 g of1-bromo-3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzene, 2.83 g ofsodium formate and 0.97 g of bis(triphenylphosphine)palladium (II)dichloride, and the mixture was stirred for 9 hours at 110° C. underbubbling carbon monoxide. To the reaction solution was added water, andextracted with ethyl acetate, filtered to remove insolubles, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=4:1) to provide 3.58 g of the objective compound as colorlesscrystals. M.p. 98-99° C.

REFERENCE EXAMPLE 423-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl-alcohol

[0483] 3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzaldehyde (3.54 g)was suspended into 35 ml of methanol, and 230 mg of sodium borohydridewas added thereto with stirring under ice-cooling, and stirred for 1.5hours at room temperature. The reaction solution was poured intoice-cold water, extracted with ethyl acetate, washed with water anddried over anhydrous magnesium sulfate. The solvent was distilled offunder reduce pressure to provide 3.54 g of the objective compound ascolorless crystals. M.p. 97-99° C.

REFERENCE EXAMPLE 433-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl-bromide

[0484] 3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}-benzyl alcohol (3.52g) was dissolved in 60 ml of dichloromethane. After addition of 3.77 gof triphenylphosphine and 5.17 g of carbon tetrabromide, the mixture wasstirred for 30 minutes at room temperature. The reaction solution wasconcentrated and the residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide3.96 g of the objective compound as colorless crystals. M.p. 101-102° C.

REFERENCE EXAMPLE 44 Diethyl3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylmalonate

[0485] To 15 ml of dry tetrahydrofuran and 7 ml of dryN,N-dimethylformamide, 0.88 g of 60% sodium hydride was added. To themixture was added dropwise 4.40 g of diethyl malonate with stirringunder ice-cooling. After 15-minute-stirring, a solution of 3.93g of3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl bromide/5 ml of drytetrahydrofuran was added and stirred for 1 hour under ice-cooling. Thereaction solution was poured into ice-cold water, extracted with ethylacetate, washed with water and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure and the residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=5:1) to provide 3.95 g of the objective compoundas colorless crystals.

[0486]¹H-NMR (CDCl₃)δ: 1.17 (6H, t), 2.25 (3H, s), 2.38 (3H, s), 3.18(2H, d), 3.62 (1H, t), 4.07 (2H, s), 4.12 (4H, q), 7.00-7.30 (6H, m),7.80-7.90 (2H, m).

REFERENCE EXAMPLE 452-[3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-propanediol

[0487] To 30 ml of dry tetrahydrofuran, 854 mg of lithium aluminiumhydride was added, and 3.94 g of diethyl3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzylmalonate/10 ml of drytetrahydrofuran was added dropwise with stirring under ice-cooling. Themixture was stirred for 1.5 hours at room temperature and cooled withice-cold water. To the mixture were added dropwise 0.85 ml of water,0.85 ml of 15% sodium hydroxide solution and 2.5 ml of watersequentially, and stirred for 15 minutes. The mixture was filtrated toremove insolubles, and the filtrate was concentrated. The residue wasdissolved into ethyl acetate and dried over anhydrous magnesium sulfate.The solvent was distilled off under reduced pressure and the residue waspurified by silica gel column chromatography (Wakogel® C-200,chloroform:methanol=20:1) to provide 2.32 g of the objective compound ascolorless crystals. M.p. 114-115° C.

REFERENCE EXAMPLE 46 Diethyl (3-fluoro-4-methylbenzoyl)aminomalonate

[0488] To a solution of 10.1 g of 3-fluoro-4-methylbenzoic acid and 15.2g of diethyl aminomalonate hydrochloride in 200 ml ofN,N-dimethylformamide, 9.7g of 1-hydroxybenzotriazole, 23 ml oftriethylamine and 13.8 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were addedsequentially, and stirred for 1 hour at room temperature. After additionof water to the reaction solution, the mixture was extracted with ethylacetate. The extract was washed with water, 10% hydrochloric acid,water, saturated aqueous sodium hydrogen carbonate solution sequentiallyand dried over anhydrous magnesium sulfate. The solvent was distilledoff under reduced pressure and the residue was crystallized by additionof isopropyl ether to provide 15.1 g of the objective compound ascolorless crystals. M.p. 102-103° C.

REFERENCE EXAMPLE 471-(p-Toluenesulfonyloxy)-3-[2-(p-tolyl)-5-trifluoromethyloxazol-4-yl]propane

[0489] 3-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]-1-propanol (6.40 g)synthesized according to the method of Kawase et. al. (Chem. Pharm.Bull., 46, 749-756(1998)) was dissolved in 35 ml of dichloromethane. Tothe solution were added sequentially 293 mg of4-(dimethylamino)pyridine, 4.7 ml of triethylamine and 5.13 g ofp-toluenesulfonyl chloride, and stirred for 3 hours at room temperature.To the reaction solution was added ethyl acetate, and washed with water,10% hydrochloric acid and an aqueous solution of saturated aqueoussodium hydrogen carbonate solution sequentially, and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure to provide 10.08 g of the objective compound as pale browncrystals. M.p. 57-58° C.

REFERENCE EXAMPLE 484-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]butanenitrile

[0490] To 40 ml of dimethylsulfoxide, 10.08 g of1-(p-toluenesulfonyloxy)-3-[2-(p-tolyl)-5-trifluoromethyloxazol-4-yl]propane,1.16 g of sodium cyanide was added and stirred for 2 hours at 90° C.Water was added to the reaction solution and the mixture was extractedwith diethyl ether, washed with water and dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure to provide6.35 g of the objective compound as pale brown crystals. M.p. 41-42.5°C.

REFERENCE EXAMPLE 49 Methyl4-[2-(p-tolyl)-5-trifluoromethyloxazol-4-yl]butanoate

[0491] 4-[2-(p-Tolyl)-5-trifluoromethyloxazol-4-yl]butanenitrile (5.28g) was dissolved in 40 ml of methanol, and stirred for 10 minutes underice-cooling under bubbling hydrogen chloride gas. After the bubbling wasstopped, the mixture was warmed to room temperature and stirred for 30minutes. To the reaction solution was added 5 ml of water, and themixture was stirred for 30 minutes, allowed to stand at room temperatureovernight. After addition of water, the reaction solution was extractedwith ethyl acetate. The extract was washed with saturated aqueous sodiumhydrogen carbonate solution, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide5.63 g of the objective compound as colorless crystals. M.p. 44.5-45° C.

REFERENCE EXAMPLE 50 Methyl 4-(fluoromethyl)benzoate

[0492] Dry acetonitrile (150 ml) was added to 25.00 g of methyl4-(bromomethyl)benzoate, 19.02 g of potassium fluoride and 9.51 g ofcalcium fluoride, and the mixture was heated to reflux for 3 days. Thereaction solution was concentrated. After addition of 200 ml ofacetonitrile, insolubles were removed by filtration, and the filtratewas concentrated again. The residue was purified by silica gel columnchromatography (YMC•GEL® SIL-60-230/70, n-hexane:ethylacetate=10:1-4:1), followed by distillation under reduced pressure toprovide 14.45 g of the objective compound as colorless oil. B.p.118.5-119° C./18 mmHg.

[0493]¹H-NMR (CDCl₃)δ: 3.93 (3H, s), 5.44 (2H, d), 7.40-7.46 (2H, m),8.03-8.09 (2H, m).

REFERENCE EXAMPLE 51 4-(Fluoromethyl)benzoic acid

[0494] To 200 ml of methanol, 8.68 g of methyl 4-(fluoromethyl)benzoatewas dissolved, and 77 ml of aqueous solution of 1 N sodium hydroxide wasadded dropwise with stirring and cooling. The mixture was then stirredfor 3.5 hours at room temperature. After the mixture was acidified with1 N hydrochloric acid, the precipitated crystals were collected byfiltration, and the filtrate was concentrated. The precipitated crystalswere combined with the residue obtained by concentrating the filtrate,and water was added thereto. The mixture was extracted with ethylacetate and dried over anhydrous magnesium sulfate. The solvent wasdistilled off under reduced pressure to provide 7.47 g of the objectivecompound as colorless crystals. M.p. 192-194° C.

REFERENCE EXAMPLE 52 4-(Fluoromethyl)benzoyl chloride

[0495] 4-(Fluoromethyl)benzoic acid (6.20 g) was dissolved in 30 ml ofbenzene, and 0.3 ml of N,N-dimethylformamide was added and then 4.4 mlof thionyl chloride was added dropwise. The mixture was stirred for 1hour at 40° C. and then heated to reflux for another 1 hour. The solventwas distilled off under reduced pressure to provide 6.70 g of theobjective compound as pale yellow oil.

REFERENCE EXAMPLE 53 Ethyl6-chloro-2-ethoxycarbonyl-2-(p-toluoylamino)hexanoate

[0496] Sodium (6.42 g) was dissolved in 390 ml of ethanol at roomtemperature. To the solution was added 78.0 g of diethylp-toluoylaminomalonate, and 47.9 g of 1-bromo-4-chlorobutane was addeddropwise under heating to reflux. The mixture was heated to reflux for20 hours. The reaction solution was concentrated. To the residue wasadded water, and the mixture was washed with ethyl acetate. Afterwashing with 10% hydrochloric acid and water sequentially, the solutionwas dried over anhydrous magnesium sulfate and concentrated. The residuewas purified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=9:1) to provide 55.7 g of the objective compoundas colorless oil.

[0497]¹H-NMR (CDCl₃)δ: 1.26 (6H, t), 1.26-1.42 (2H, m), 1.72-1.86 (2H,m), 2.41 (3H, s), 2.44-2.52 (2H, m), 3.51 (2H, t), 4.28 (4H, q),7.24-7.28 (2H, m), 7.48 (1H, s), 7.71-7.75 (2H, m).

REFERENCE EXAMPLE 54 6-Chloro-2-(p-toluoylamino)hexanoic acid

[0498] Ethyl 6-chloro-2-ethoxycarbonyl-2-(p-toluoylamino)hexanoate(103.2 g) was dissolved in 412 ml of ethanol, and a solution of 24.5 gof sodium hydroxide/98 ml of water was added, and heated to reflux for16 hours. The reaction solution was concentrated. To the residue wasadded ethyl acetate. The mixture was acidified with hydrochloric acidand extracted with ethyl acetate. The extract was washed with water,dried over anhydrous magnesium sulfate and concentrated to provide 80.0g of colorless gum. To the resulting gum, 75 ml of acetic acid was addedand heated to reflux for 10 hours. After the mixture was stirred andstood to cool, the precipitated crystals were washed with ethyl acetateand recrystallized from acetic acid to provide 26.0 g of the objectivecompound as colorless crystals. M.p. 177-181° C.

REFERENCE EXAMPLE 55 8-Chloro-4-(p-toluoylamino)-3-octanone

[0499] 6-Chloro-2-(p-toluoylamino)hexanoic acid (10.0 g) was dissolvedin 15 ml of dry pyridine, and 15 ml of propionic anhydride was added andstirred for 2.5 hours at 90° C. To the mixture was added 15 ml of waterslowly so that the maximum temperature did not exceed 85° C., andstirred for 20 minutes at 80° C. The reaction solution was cooled,poured into ice-cold water and extracted with diethyl ether. The extractwas washed with 10% hydrochloric acid, an aqueous solution of saturatedsodium hydrogen carbonate and brine sequentially, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=8:1-4:1) to provide 6.0 g of the objective compound as colorlesscrystals. M.p. 85-86° C.

REFERENCE EXAMPLE 56 4-(4-Chlorobutyl)-5-ethyl-2-(p-tolyl)oxazole

[0500] To 150 ml of toluene, 6.5 g of8-chloro-4-(p-toluoylamino)-3-octanone was dissolved, and 4.1 ml ofphosphorus oxychloride was added and heated to reflux for 1.5 hours. Thereaction solution was cooled, poured into ice-cold water and extractedwith ethyl acetate. The extract was washed with an aqueous solution ofsaturated sodium hydrogen carbonate and brine sequentially, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=8:1) to provide 5.5 g of the objective compound as yellowishcrystals.

[0501]¹H-NMR (CDCl₃)δ: 1.27 (3H, t), 1.78-1.87 (4H, m), 2.38 (3H, s),2.52 (2H, t), 2.67 (2H, q), 3.57 (2H, t), 7.23 (2H, d), 7.84-7.89 (2H,m).

REFERENCE EXAMPLE 57 Diethyl 4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]butylmalonate

[0502] To 32.8 ml of 21% sodium ethoxide-ethanol solution, 16.7 ml ofdiethyl malonate was added under heating to reflux. Then, 5.0 g of4-(4-chlorobutyl)-5-ethyl-2-(p-tolyl)oxazole/5 ml of ethanol was addeddropwise and the mixture was heated to reflux for 7 hours under argonatmosphere. The reaction solution was poured into ice-cold water andextracted with ethyl acetate, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=10:1) to provide2.65 g of the objective compound as yellow oil.

[0503]¹H-NMR (CDCl₃)δ: 1.25 (6H, t), 1.29 (3H, t), 1.35-1.46 (2H, m),1.65-1.73 (2H, m), 1.88-1.99 (2H, m), 2.39 (3H, s), 2.48 (2H, t), 2.66(2H, q), 3.32 (1H, t), 4.13-4.26 (4H, m), 7.22 (2H, d), 7.87 (2H, d).

REFERENCE EXAMPLE 58

[0504] The following compounds were prepared by the same procedure asdescribed in the after-mentioned Example 6.

[0505]2,2-Dimethyl-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane,

[0506] Methyl 4-(5-methyl-2-phenyloxazol-4-yl)butyrate and

[0507] Methyl 3-(5-methyl-2-phenyloxazol-4-yl)propionate.

REFERENCE EXAMPLE 59 1-(o-Toluoylamino)-2-propanol

[0508] To 100 ml of a solution of 5.83 g of 1-amino-2-propanol intoluene, 18.0 ml of triethylamine was added, and 10 ml of a solution of10.00 g of o-toluoyl chloride in toluene was added dropwise slowly withstirring under ice-cooling. After 30-minute-stirring, the ice-bath wasremoved, and the mixture was stirred for additional 1 hour at roomtemperature. To the reaction solution was added water, and the mixturewas extracted with ethyl acetate. The extract was washed with 10%hydrochloric acid, ice-cold water and saturated aqueous sodium hydrogencarbonate solution sequentially, dried over anhydrous magnesium sulfateand the solvent was distilled off under reduced pressure. The residuewas crystallized by addition of diethyl ether to provide 7.25 g of theobjective compound as colorless crystals. M.p. 78-81° C.

[0509] The following compounds were prepared by the same procedure asdescribed in Reference Example 59.

[0510] 1-(4-Fluoromethylbenzoylamino)-2-propanol,

[0511] 1-(m-Toluoylamino)-2-propanol and

[0512] 1-(Cyclohexylcarbonylamino)-2-propanol.

REFERENCE EXAMPLE 60 1-(o-Toluoylamino)-2-propanone

[0513] Pyridinium chlorochromate (15.91 g) was added to 143 ml of asuspension of 7.13 g of 1-(o-toluoylamino)-2-propanol and 15.91 g ofcelite in dichloromethane with stirring. The mixture was stirred for 4hours at room temperature. The reaction solution was purified by silicagel column chromatography (Wakogel® C-200, chloroform) and the solventwas distilled off under reduced pressure. The eluate was purified againby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=1:2) to provide 5.73 g of the objective compound as colorlesscrystals. M.p. 65-66° C.

[0514] The following compounds were prepared by the same procedure asdescribed in Reference Example 60.

[0515] 1-(2,4-Dimethylbenzoylamino)-2-propanone,

[0516] 1-(4-Fluoromethylbenzoylamino)-2-propanone,

[0517] 1-(m-Toluoylamino)-2-propanone,

[0518] 1-(3,4-Dimethylbenzoylamino)-2-propanone,

[0519] 1-(4-Methoxybenzoylamino)-2-propanone and

[0520] 1-(Cyclohexylcarbonylamino)-2-propanone.

REFERENCE EXAMPLE 61 Methylc-5-[5-acetyl-5-(o-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate

[0521] Under argon atmosphere, 40 ml of a suspension of 1.18 g of 60%sodium hydride in N,N-dimethylformamide was cooled to −25° C. in dryice-acetone bath, and then 15 ml of a solution of 5.65 g of1-(o-toluoylamino)-2-propanone in N,N-dimethylformamide was addeddropwise slowly. After 1-hour-stirring, 5 ml of a solution of 10.09 g ofmethyl c-5-(4-iodobutyl)-2-methyl-1,3-dioxane-r-2-carboxylate inN,N-dimethylformamide was added dropwise slowly, and the mixture wasstirred for another 1 hour. To the reaction solution was added 1 ml of 1N hydrochloric acid, and then water, and the mixture was extracted withdiethyl ether. The extract was washed with aqueous solution of 0.5%aqueous sodium hydroxide solution, dried over anhydrous magnesiumsulfate and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=1:1) to provide 6.38 g of the objectivecompound as colorless oil.

[0522]¹H-NMR (CDCl₃)δ: 1.01-1.08 (2H, m), 1.22-1.39 (4H, m), 1.51 (3H,s), 1.62-1.71 (2H, m), 1.97-2.09 (1H, m), 2.28 (3H, s), 2.44 (3H, s),3.39 (2H, t), 3.83 (3H, s), 3.94 (2H, dd), 4.84 (1H, q), 6.49 (1H, d),7.22-7.42 (4H, m).

[0523] The following compounds were prepared by the same procedure asdescribed in Reference Example 61.

[0524] Methylc-5-[5-acetyl-5-(2,4-dimethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0525] Methylc-5-[5-acetyl-5-(4-fluoromethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0526] Methylc-5-[5-acetyl-5-(m-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0527] Methylc-5-[5-acetyl-5-(3,4-dimethylbenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0528] Methylc-5-[5-acetyl-5-(4-methoxybenzoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate,

[0529] Methylc-5-[5-acetyl-5-(2-thenoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylateand

[0530] Methylc-5-[5-acetyl-5-(cyclohexylcarbonylamino)-pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate.

REFERENCE EXAMPLE 62 1-(3,4-Dimethylbenzoylamino)-2-propanol

[0531] To 30 ml of a solution of 5.00 g of 3,4-dimethylbenzoic acid and2.75 g of 1-amino-2-propanol in N,N-dimethylformamide, 4.95 g of1-hydroxybenzotriazole, 6.96 ml of triethylamine and 7.02 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were addedsequentially, and stirred for 15 hours at room temperature. Afteraddition of water, the reaction solution was extracted with ethylacetate, washed with 10% hydrochloric acid, ice-cold water and aqueoussolution of saturated sodium hydrogen carbonate sequentially, and driedover anhydrous magnesium sulfate. The solvent was distilled off underreduced pressure to provide 6.28 g of the objective compound ascolorless crystals. M.p. 77-78° C.

[0532] The following compounds were prepared by the same procedure asdescribed in Reference Example 62.

[0533] 1-(2,4-Dimethylbenzoylamino)-2-propanol and

[0534] 1-(4-Methoxybenzoylamino)-2-propanol.

REFERENCE EXAMPLE 63 Methyl 2-(2-thenoylamino)acetate

[0535] To 250 ml of a suspension of 12.56 g of methyl 2-aminoacetatehydrochloride in dichloromethane, 20.24 g of triethylamine was added,and stirred for 30 minutes at room temperature. After ice-cooling, 20 mlof a solution of 14.66 g of 2-thenoyl chloride in dichloromethane wasadded dropwise slowly. The ice-bath was removed and the mixture wasstirred for 14 hours at room temperature. The precipitated crystals werecollected by filtration and washed with dichloromethane. The solvent wasremoved from the filtrate by distillation under reduced pressure. To theresidue was added t-butyl methyl ether to precipitate. The both productswere combined to provide 17.20 g of the objective compound as brownishcrystals.

[0536]¹H-NMR (CDCl₃)δ: 3.80 (3H, s), 4.23 (2H, d), 6.62 (1H, br), 7.09(1H, dd), 7.50 (1H, dd), 7.57 (1H, dd).

REFERENCE EXAMPLE 64 Sodium 2-(2-thenoylamino)acetate

[0537] To 200 ml of a solution of 16.70 g of methyl2-(2-thenoylamino)acetate in methanol, 20 ml of aqueous solution of 4.02g sodium hydroxide was added, and heated to reflux for 30 minutes. Thesolvent was distilled off under reduced pressure. The residue wascrystallized by addition of isopropanol to provide 18.03 g of theobjective compound as pale yellow crystals.

REFERENCE EXAMPLE 65 1-(2-Thenoylamino)-2-propanone

[0538] To 44.0 ml of a suspension of 16.70 g of sodium2-(2-thenoylamino)acetate in β-picoline, 42.7 ml of acetic anhydride wasadded, and stirred for 3 hours at room temperature. After ice-cooling,26.3 ml of ethanol, 129.7 ml of water and 45.2 ml of conc. hydrochloricacid were slowly added dropwise in sequence, and the mixture was stirredfor 15 minutes as it is. After removal of ice-bath, the mixture wasstirred for another 15 minutes at room temperature. Water (250 ml) wasadded and the precipitated crystals were collected, and washed withwater. To the crystals was added 37.0 ml of water, and the mixture washeated to reflux for 1 hour. After 14.0 g of sodium chloride was added,the mixture was heated to reflux for another 1 hour. The reactionsolution was extracted with ethyl acetate, and dried over anhydrousmagnesium sulfate. After addition of activated carbon(Kyoryoku-sirasagi® MOIWY433), the mixture was stirred for 30 minutes atroom temperature. The solvent was distilled off under reduced pressure.The residue was crystallized by addition of t-butyl methyl ether toprovide 7.15 g of the objective compound as pale brown crystals.

[0539]¹H-NMR (CDCl₃)δ: 2.27 (3H, s), 4.34 (2H, d), 6.80 (1H, br), 7.09(1H, dd), 7.50 (1H, dd), 7.57 (1H, dd).

REFERENCE EXAMPLE 664-[5,5-Bis(bromomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole

[0540] To 15 ml of a solution of 2.25 g of4-[5,5-bis(hydroxymethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole inN,N-dimethylformamide, 3.92 ml of γ-colidine, 2.57 g of lithium bromideand 2.3 ml of methanesulfonyl chloride were added sequentially, andstirred under heating for 2.5 hours at 80° C. To the reaction solutionwas added water, and the mixture was extracted with ethyl acetate,washed with brine, dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduce pressure. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=9:1) to provide 1.45 g of the objective compoundas brown oil.

[0541]¹H-NMR (CDCl₃)δ: 1.30-1.55 (2H, m), 1.60-1.85 (4H, m), 1.95-2.15(1H, m), 2.31 (3H, s), 2.38 (3H, s), 2.49 (2H, t), 2.82-3.05 (4H, m),7.38-7.45 (2H, m), 7.94-8.01 (2H, m).

REFERENCE EXAMPLE 674-[5,5-Bis(acetylthiomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole

[0542] To 4 ml of a solution of 923 mg of4-[5,5-bis(bromomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole inpolyethylene glycol #200, 1.18 g of potassium thiolacetate was added,and stirred under heating for 1.5 hours at 80° C. To the reactionsolution was added water, and the mixture was extracted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate andthe solvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=9:1) to provide 830 mg of the objective compoundas brown oil.

[0543]¹H-NMR (CDCl₃)δ: 1.35-1.50 (4H, m), 1.55-1.70 (2H, m), 1.75-1.95(1H, m), 2.32 (3H, s), 2.33 (6H, s), 2.38 (3H, s), 2.47 (2H, t),2.82-3.05 (4H, m), 7.20-7.25 (2H, m), 7.84-7.89 (2H, m).

[0544] The following compound was prepared by the same procedure asdescribed in Reference Example 67.

[0545] 5-Methyl-4-(6-acetylthiohexyl)-2-(p-tolyl)oxazole.

REFERENCE EXAMPLE 684-[5,5-Bis(mercaptomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole

[0546] To 8 ml of a solution of 830 mg of4-[5,5-bis(acetylthiomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole inmethanol, 8 ml of aqueous 1 N sodium hydroxide solution was added, andheated to reflux for 1 hour. The reaction solution was acidified with 1N hydrochloric acid, extracted with dichloromethane and dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure to provide 635 mg of the objective compound as pale yellow oil.

[0547]¹H-NMR (CDCl₃)δ: 1.25-1.95 (9H, m), 2.31 (3H, s), 2.38 (3H, s),2.48 (2H, t), 2.55-2.85 (4H, m), 7.16-7.24 (2H, m), 7.81-7.89 (2H, dd).

REFERENCE EXAMPLE 69 Ethyl 6-iodohexanoate

[0548] To 112 ml of a solution of 13.38 g of ethyl 6-bromohexanoate inacetone, 26.97 g of sodium iodide was added and heated to reflux for 18hours. The reaction solution was cooled, filtered to remove insolublesand washed with acetone. The filtrate was concentrated and, afteraddition of water, extracted with ethyl acetate. The organic layer waswashed with water and brine sequentially, dried over anhydrous magnesiumsulfate and concentrated to provide 16.21 g of the objective compound asred-yellow oil.

[0549]¹H-NMR (CDCl₃)δ: 1.26 (3H, t), 1.39-1.51 (2H, m), 1.58-1.73 (2H,m), 1.78-1.92 (2H, m), 2.31 (2H, t), 3.19 (2H, t), 4.13 (2H, q).

REFERENCE EXAMPLE 70 Ethyl 7-acetyl-7-(p-toluoylamino)heptanoate

[0550] A suspension (100 ml) of 60% sodium hydride (2.64 g) inN,N-dimethylformamide was cooled to −18° C. with an ice-sodium chloridebath, and 31 ml of a solution of 12.62 g of1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was addeddropwise slowly. After 1-hour-stirring, 31 ml of a solution of 16.21 gof ethyl 6-iodohexanoate in N,N-dimethylformamide was added dropwiseslowly. The ice-bath was removed and the mixture was stirred for 18hours at room temperature. After addition of ice-cold water, thereaction solution was extracted with ethyl acetate, washed with waterand brine sequentially, dried over anhydrous magnesium sulfate and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=3:1) to provide 13.13 g of the objective compoundas yellow oil.

[0551]¹H-NMR (CDCl₃)δ: 1.20-1.45 (4H, m), 1.24 (3H, t), 1.54-1.77 (3H,m), 2.01-2.08 (1H, m), 2.23-2.31 (2H, t), 2.40 (3H, s), 2.78 (3H, s),4.11 (2H, q), 4.18-4.90 (1H, m), 6.90 (1H, d), 7.25 (2H, d), 7.71 (2H,d).

REFERENCE EXAMPLE 71 Ethyl 2-(6-iodohexyloxy)-2-methylpropionate

[0552] To 76 ml of a solution of 12.16 g of ethyl2-(6-bromohexyloxy)-2-methylpropionate in acetone, 18.52 g of sodiumiodide was added, and heated to reflux for 18 hours. The reactionsolution was cooled, filtered to remove insolubles and washed withacetone. The filtrate was concentrated and, after addition of water,extracted with ethyl acetate. The organic layer was washed with waterand brine sequentially, dried over anhydrous magnesium sulfate andconcentrated to provide 14.46 g of the objective compound as red-yellowoil.

[0553]¹H-NMR (CDCl₃)δ: 1.29 (3H, t), 1.37-1.40 (4H, m), 1.41 (6H, s),1.55-1.62 (2H, m), 1.80-1.87 (2H, m), 3.19 (2H, t), 3.56 (2H, t), 4.12(2H, q).

REFERENCE EXAMPLE 72 Ethyl2-[7-acetyl-7-(p-toluoylamino)heptyloxy]-2-methylpropionate

[0554] A suspension (70 ml) of 1.81 g of 60% sodium hydride inN,N-dimethylformamide was cooled to −18° C. with ice-sodium chloridebath, and 21 ml of a solution of 8.67 g of1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was addedslowly. After 1-hour-stirring, 21 ml of a solution of 14.10 g of ethyl2-(6-iodohexyloxy)-2-methylpropionate in N,N-dimethylformamide was addeddropwise slowly. The bath was removed and the mixture was stirred foradditional 18 hours at room temperature. The reaction solution was,after addition of ice-cold water, extracted with ethyl acetate, washedwith water and brine sequentially, dried over anhydrous magnesiumsulfate, and the solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=3:1) to provide 12.20 g of the objectivecompound as yellow crystals.

[0555]¹H-NMR (CDCl₃)δ: 1.23-1.41 (6H, m), 1.27 (3H, t), 1.39 (6H, s),1.51-1.57 (2H, m), 1.71-1.74 (1H, m), 2.01-2.08 (1H, m), 2.27 (3H, s),2.40 (3H, s), 3.32 (2H, t), 4.17 (2H, q), 4.80-4.90 (1H, m), 6.89 (1H,d), 7.25 (2H, d), 7.71 (2H, d).

REFERENCE EXAMPLE 73 7-(Benzoylamino)-7-carboxy-(E)-4-heptenoic acid

[0556] To 170 ml of a solution of 8.50 g of diethyl[5-(benzoylamino)-5,5-bis(ethoxycarbonyl)-(E)-2-pentenyl]-malonate inethanol, 34 ml of aqueous solution of sodium hydroxide (5.53 g) wasadded, and heated to reflux for 20 hours. The reaction solution wasconcentrated, and the residue was, after addition of water, washed withdiethyl ether. The aqueous layer was acidified with hydrochloric acid,extracted with ethyl acetate, dried over anhydrous magnesium sulfate andconcentrated to provide 6.58 g of pale yellow oil. The resulting oil wasdissolved in 90 ml of ethyl acetate. To the solution was added 90 ml ofxylene and stirred for 15 hours at 130° C. The solvent was distilled offunder reduced pressure, and the resulting crystals were washed withisopropyl ether to provide 4.52 g of the objective compound as colorlesscrystals. M.p. 138° C.

EXAMPLE 1 Methyl2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

[0557] 4-[5,5-Bis(hydroxymethyl)pentyl]-5-methyl-2-phenyloxazole (36 g)was dissolved in 432 ml of acetonitrile, and 25.4 g of methyl pyruvatewas added. To the mixture, 35.3 g of boron trifluoride etherate (about47%) was added with stirring at room temperature and refluxed for 2hours. The reaction solution was cooled, poured into an ice-cold watersolution of sodium hydrogencarbonate and extracted with ethyl acetate.The organic layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=7.5:1) andfractions eluted earlier were concentrated to provide 16.5 g of theobjective compound as colorless oil.

[0558]¹H-NMR (CDCl₃)δ: 1.00-1.12 (2H, m), 1.22-1.40 (2H, m), 1.55-1.70(5H, m), 1.90-2.20 (1H, m), 2.30 (3H, s), 2.45 (2H, t), 3.39 (2H, t),3.82 (3H, s), 3.95 (2H, dd), 7.37-7.47 (3H, m), 7.92-8.03 (2H, m).

EXAMPLE 2 Methyl2-methyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

[0559] The latter fractions of Example 1 were collected and concentratedto obtain 11 g of the residue, which was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=7.5:1) again toprovide 0.83 g of the objective compound as colorless oil.

[0560]¹H-NMR (CDCl₃)δ: 1.33-1.44 (3H, m), 1.51 (3H, s), 1.63-1.78(4H,m), 2.33 (3H, s), 2.51 (2H, t), 3.75-3.81 (2H, m), 3.83 (3H, s),3.91-3.99 (2H, m), 7.38-7.45 (3H, m), 7.96-8.01 (2H, m).

[0561] The following compounds were prepared by the same procedure asdescribed in Examples 1 and 2.

[0562] Methylc-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0563] Methylt-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0564] Methyl2-ethyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)-butyl]-1,3-dioxane-r-2-carboxylate,

[0565] Methyl2-isobutyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0566] Methyl2,5-dimethyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0567] Methyl2,5-dimethyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0568] Methyl5-ethyl-2-methyl-c-5-[4-(5-methyl-2-phenyl-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0569] Methyl5-ethyl-2-methyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0570] Methyl2-methyl-c-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylate,

[0571] Methyl2-methyl-t-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylate,

[0572] Methyl2-methyl-c-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-r-2-carboxylate,

[0573] Methyl2-methyl-c-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylate,

[0574] Methyl2-methyl-c-5-{3-[(5-methyl-2-phenyloxazol-4-yl)-methyl]phenyl}-1,3-dioxane-r-2-carboxylate,

[0575] Methyl2-methyl-c-5-{4-[2-(p-tolyl)-5-trifluoromethyl-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0576] Methyl2-methyl-c-5-{4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylateand

[0577] Ethyl2-ethyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate.

EXAMPLE 3 Methyl2-methyl-c-5-[4-(2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

[0578] To 5 ml of acetonitrile, 1.25 g of4-[5,5-bis(hydroxy-methyl)pentyl]-2-phenyloxazole was dissolved, and 927mg of methyl pyruvate was added. To the mixture, 1.3 g of borontrifluoride etherate (about 47% ) was added with stirring at roomtemperature, and stirred for 30 hours at room temperature. The reactionsolution was poured into ice-cold water solution of sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:isopropyl ether=1:1) and thefractions eluted earlier were concentrated to provide 450 mg g of theobjective compound as white crystals. M.p. 71-74° C.

[0579]¹H-NMR (CDCl₃)δ: 1.01-1.12 (2H, m), 1.27-1.43 (2H, m), 1.51 (3H,s), 1.59-1.74 (2H, m), 1.90-2.20 (1H, m), 2.56 (2H, t), 3.39 (2H, t),3.83 (3H, s), 3.96 (2H, dd), 7.41-7.47 (4H, m), 7.99-8.05 (2H, m).

EXAMPLE 4 Methyl2-methyl-t-5-[4-(2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate

[0580] The latter fractions of Example 3 were collected andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:isopropyl ether=1:1) again toprovide 110 mg of the objective compound as colorless oil.

[0581]¹H-NMR (CDCl₃)δ: 1.25-1.48 (2H, m), 1.51 (3H, s), 1.63-1.80 (5H,m), 2.62 (2H, t), 3.76-3.86 (5H, m), 3.92-4.00 (2H, m), 7.41-7.47 (4H,m), 8.00-8.05 (2H, m).

EXAMPLE 5 Methyl2-methyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-2-carboxylate

[0582] To 5 ml of acetonitrile, 297 mg of4-{3-[2,2-bis-(hydroxymethyl)ethyl]benzyl}-5-methyl-2-phenyloxazole and369 mg of methyl pyruvate were added. To the mixture was added 544 mg ofboron trifluoride etherate (about 47% ) with stirring at roomtemperature, and stirred for 14 hours at room temperature. The reactionsolution was poured into an ice-cold water solution of sodiumhydrogencarbonate and extracted with ethyl acetate. The organic layerwas washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide185 mg of a mixture (cis:trans=2.5:1, based on NMR integral value) ascolorless oil.

EXAMPLE 6 Methyl2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

[0583] Methylc-5-[5-acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylate(0.85 g) was dissolved in 17 ml of toluene. After addition of 644 mg ofphosphorus oxychloride, the mixture was heated to reflux for 2.5 hours.The reaction solution was cooled, poured into ice-cold water,neutralized with aqueous solution of sodium hydrogencarbonate, extractedwith ethyl acetate, washed with brine, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, chloroform: methanol=100:1) to provide0.42 g of the objective compound as white crystals. M.p. 92-94° C.

[0584] Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C, 68.20; H, 7.54;N, 3.61. Found (%): C, 68.07; H, 7.43; N, 3.65.

[0585] The following compounds were prepared by the same procedure asdescribed in Example 6.

[0586] Methyl2-methyl-c-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylate,

[0587] Methyl2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate,

[0588] Methyl2-methyl-c-5-[5-(5-methyl-2-phenyloxazol-4-yl)pentyl]-1,3-dioxane-r-2-carboxylate,

[0589] Methylc-5-{4-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylate,

[0590] Methylc-5-{4-[2-(4-tert-butylphenyl)-5-methyloxazol-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylate,

[0591] Methyl2-methyl-c-5-{4-[5-methyl-2-(4-trifluoromethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0592] Methyl2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-2-butenyl]-1,3-dioxane-r-2-carboxylate,

[0593] Methyl2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionate,

[0594] Methyl2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate,

[0595] Methyl2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexynyloxy]propionate,

[0596] Methyl2-{6-[2-(4-chlorophenyl)-5-methyloxazol-4-yl]hexyloxy}-2-methylpropionate,

[0597] Methyl2-{6-[2-(4-fluorophenyl)-5-methyloxazol-4-yl]hexyloxy}-2-methylpropionate,

[0598] Methyl2-{6-[2-(4-tert-butylphenyl)-5-methyloxazol-4-yl]-hexyloxy}-2-methylpropionate,

[0599] Methyl2-methyl-2-[7-(5-methyl-2-phenyloxazol-4-yl)heptyloxy]propionate,

[0600] Methyl2-methyl-2-[5-(5-methyl-2-phenyloxazol-4-yl)pentyloxy]propionate,

[0601] Methyl2-[6-(5-ethyl-2-phenyloxazol-4-yl)hexyloxy]-2-methylpropionate,

[0602] Methyl2-methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionate,

[0603] Methyl2-methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propionate,

[0604] Methyl2-methyl-c-5-{4-[5-methyl-2-(4-chlorophenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0605] Methyl2-methyl-c-5-{5-[5-methyl-2-(p-tolyl)oxazol-4-yl]pentyl}-1,3-dioxane-r-2-carboxylate,

[0606] Methyl2-methyl-c-5-{4-[5-methyl-2-(3-fluoro-4-methylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0607] Methyl2-methyl-c-5-{4-[5-methyl-2-(4-ethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0608] Methyl2-methyl-c-5-{4-[5-methyl-2-(2,4-dimethyl-phenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0609] Methyl2-methyl-c-5-{4-[2-(4-fluoromethylphenyl)-5-methyloxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0610] Methyl2-methyl-c-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0611] Methyl2-methyl-c-5-{4-[5-methyl-2-(o-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0612] Methyl2-methyl-c-5-{4-[5-methyl-2-(3,4-dimethyl-phenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0613] Methyl2-methyl-c-5-{4-[5-methyl-2-(4-methoxyphenyl)-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0614] Methyl2-methyl-c-5-{4-[5-methyl-2-(2-thienyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate,

[0615] Methyl2-methyl-c-5-{4-[2-cyclohexyl-5-methyloxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylateand

[0616] Ethyl2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate.

EXAMPLE 7 Methyl 2-methyl-2-[6-(2-phenyloxazol-4-yl)hexyloxy]-propionate

[0617] A mixture of 956 mg of benzamide and 1.1 g of methyl2-(8-chloro-7-oxooctyloxy)-2-methylpropionate was stirred for 2 hours at120° C. The reaction solution was cooled, dissolved in ethyl acetate,washed by adding sodium hydrogencarbonate, washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane:ethylacetate=9:1) to provide 658 mg of the objective compound as colorlessoil.

[0618]¹H-NMR (CDCl₃)δ: 1.36-1.50 (10H, m), 1.55-1.80 (4H, m), 2.54-2.63(2H, m), 3.35 (2H,t), 3.73 (3H, s), 7.41-7.47 (4H, m), 7.99-8.05 (2H,m).

[0619] The following compounds were prepared by the same procedure asdescribed in Example 7.

[0620] Methyl 2-methyl-2-[7-(2-phenyloxazol-4-yl)heptyloxy]propionate,

[0621] Methyl2-{7-[2-(4-chlorophenyl)oxazol-4-yl]heptyloxy}-2-methylpropionate,

[0622] Methyl2-{7-[2-(4-fluorophenyl)oxazol-4-yl]heptyl-oxy}-2-methylpropionate,

[0623] Methyl2-{6-[2-(4-fluorophenyl)oxazol-4-yl]hexyloxy}-2-methylpropionate and

[0624] Methyl 2-methyl-2-[8-(2-phenyloxazol-4-yl)octyloxy]propionate.

EXAMPLE 8 Methyl2-methyl2-[7-(2-phenyltiazole-4-yl)heptyloxy]-propionate

[0625] A mixture of 783 mg of thiobenzamide and 1.0 g methyl2-(9-chloro-8-oxononyloxy)-2-methylpropionate were stirred for 2 hoursat 120° C. The reaction solution was cooled and dissolved in ethylacetate, washed by adding sodium hydrogencarbonate, washed with water,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=9:1) to provide 963 mg of the objective compoundas pale yellow oil.

[0626]¹H-NMR (CDCl₃)δ: 1.36-1.39 (6H, m), 1.42 (6H, s), 1.54-1.61 (2H,m), 1.72-1.80 (2H, m), 2.78-2.86 (2H, m), 3.31-3.38 (2H, m), 3.73 (3H,s), 6.87 (1H, s), 7.39-7.46 (3H, m) 7.91-7.96 (2H, m).

[0627] The following compound was prepared by the same procedure asdescribed in Example 8.

[0628] Methyl 2-methyl-2-[8-(2-phenylthiazole-4-yl)octyloxy]-propionate.

EXAMPLE 92-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0629] Methyl2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate(15.76 g) was dissolved in 215 ml of methanol, and a solution of 2.53 gof sodium hydroxide/28 ml of water was added and the mixture wasrefluxed for 4 hours. The reaction solution was cooled, poured intoice-cold water, acidified with dilute hydrochloric acid and extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous magnesium sulfate and concentrated. The residue was dissolvedwith heat in toluene/n-hexane and stood to cool. The precipitate wascollected by filtration to provide 13.52 g of the objective compound.

[0630]¹H-NMR (CDCl₃)δ: 1.00-1.15 (2H, m), 1.25-1.45 (2H, m), 1.50-1.70(5H, m), 1.90-2.20 (1H, m), 2.32 (3H, s), 2.52 (2H, t), 3.49 (2H, dd),3.99 (2H, dd), 7.40-7.50 (3H, m), 7.90-8.05 (2H, m), 9.70 (1H, br).Elemental analysis for C₂₀H₂₅NO₅ Calcd. (%): C, 66.84; H, 7.01; N, 3.90.Found (%): C, 66.76; H, 7.09; N, 3.82.

EXAMPLE 102-Methyl-c-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-r-2-carboxylicacid

[0631] Methyl2-methyl-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-2-carboxylate(a mixture of cis:trans=3:1) (185 mg) was dissolved in 5 ml of methanol,and 0.5 ml of 2N sodium hydroxide was added and refluxed for 1 hour. Thereaction solution was cooled, poured into ice-cold water, acidified withdilute hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with brine, dried over anhydrous magnesium sulfate andconcentrated. To the residue was added ether. The precipitated crystalswere collected by filtration, recrystallized from acetonitrile and driedto provide 109 mg of the objective compound as white crystals. M.p.147-149° C.

[0632] Elemental analysis for C₂₄H₂₅NO₅ Calcd. (%): C, 70.75; H, 6.18;N, 3.44. Found (%): C, 70.85; H, 6.26; N, 3.33.

EXAMPLE 112-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0633] Methyl2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate(250 mg) was dissolved in 2.5 ml of methanol, and a solution of 51 mg ofsodium hydroxide/0.6 ml of water was added and refluxed for 1 hour. Thereaction solution was cooled, poured into ice-cold water, acidified withdilute hydrochloric acid and extracted with ethyl acetate. Theorganic-layer was washed with brine, dried over anhydrous magnesiumsulfate and concentrated. To the residue was added ether. Theprecipitates were collected by filtration, dissolved in acetonitrileunder heating and allowed to stand to cool. The precipitates werecollected by filtration and dried to provide 196 mg of the objectivecompound.

[0634] Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C, 67.54; H, 7.29;N, 3.75. Found (%): C, 67.57; H, 7.25; N, 3.76.

[0635] The compounds of Examples 12-52 were prepared by the sameprocedure as described in Example 11.

EXAMPLE 122-Methyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0636] M.p. 135-140° C.

[0637]¹H-NMR (CDCl₃)δ: 1.38-1.50 (3H, m), 1.56 (3H, s), 1.60-1.80 (4H,m), 2.33 (3H, s), 2.54 (2H, t), 3.79 (2H, dd), 4.03 (2H, dd), 7.20 (1H,br), 7.40-7.50 (3H, m), 7.90-8.10 (2H, m). Elemental analysis forC₂₀H₂₅NO₅ Calcd. (%): C, 66.84; H, 7.01; N, 3.90. Found (%): C, 67.35;H, 7.00; N, 3.77.

EXAMPLE 132-Methyl-c-5-[5-(5-methyl-2-phenyloxazol-4-yl)pentyl]-1,3-dioxane-r-2-carboxylicacid

[0638] M.p. 135-137° C. Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C,67.54; H, 7.29; N, 3.75. Found (%): C, 67.44; H, 7.34; N, 3.77.

EXAMPLE 142-Methyl-c-5-[4-(2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0639] Elemental analysis for C₁₉H₂₃NO₅ Calcd. (%): C, 66.07; H, 6.71;N, 4.06. Found (%): C, 66.09; H, 6.75; N, 4.03.

EXAMPLE 15c-5-[4-(5-Methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0640] M.p. 119-121° C. Elemental analysis for C₁₉H₂₃NO₅ Calcd. (%): C,66.07; H, 6.71; N, 4.06. Found (%): C, 66.02; H, 6.87; N, 4.18.

EXAMPLE 16t-5-[4-(5-Methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0641] M.p. 103-105° C. Elemental analysis for C₁₉H₂₃NO₅ Calcd. (%): C,66.07; H, 6.71; N, 4.06. Found (%): C, 66.07; H, 6.99; N, 4.04.

EXAMPLE 172-Methyl-t-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0642] M.p. 120-122° C. Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C,67.54; H, 7.29; N, 3.75. Found (%): C, 67.61; H, 7.35; N, 3.74.

EXAMPLE 18c-5-{4-[2-(4-tert-Butylphenyl)-5-methyloxazol-4-yl]butyl}-2-methyl-1,3-dioxane-r-2-carboxylicacid

[0643] Elemental analysis for C₂₄H₃₃NO₅ Calcd. (%): C, 69.37; H, 8.00;N, 3.37. Found (%): C, 69.26; H, 7.96; N, 3.43.

EXAMPLE 19c-5-14-[2-(4-Fluorophenyl)-5-methyloxazol-4-yl]butyl)-2-methyl-1,3-dioxane-r-2-carboxylicacid

[0644] M.p. 138-139.5° C. Elemental analysis for C₂₀H₂₄FNO₅ Calcd. (%):C, 63.65; H, 6.41; N, 3.71. Found (%): C, 63.62; H, 6.58; N, 3.69.

EXAMPLE 202-Methyl-c-5-{4-[5-methyl-2-(4-trifluoromethylphenyl)-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0645] Elemental analysis for C₂₁H₂₄F₃NO₅ Calcd. (%): C, 59.01; H, 5.66;N, 3.28. Found (%): C, 59.14; H, 5.83; N, 3.29.

EXAMPLE 212-Ethyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0646] Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C, 67.54; H, 7.29;N, 3.75. Found (%): C, 67.05; H, 7.24; N, 3.60.

EXAMPLE 222-Isobutyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0647] M.p. 126-130° C. Elemental analysis for C₂₃H₃₁NO₅ Calcd. (%): C,68.80; H, 7.78; N, 3.49. Found (%): C, 68.72; H, 7.88; N, 3.45.

EXAMPLE 232,5-Dimethyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0648] M.p. 147-150° C. Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C,67.54; H, 7.29; N, 3.75. Found (%): C, 68.17; H, 7.76; N, 3.46.

EXAMPLE 242,5-Dimethyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0649] M.p. 142-144° C. Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C,67.54; H, 7.29; N, 3.75. Found (%): C, 67.35; H, 7.37; N, 3.44.

EXAMPLE 255-Ethyl-2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0650] M.p. 155-158° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 68.18; H, 7.59; N, 3.49.

EXAMPLE 265-Ethyl-2-methyl-t-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid

[0651] M.p. 126-130° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 67.77; H, 7.57; N, 3.47.

EXAMPLE 272-Methyl-c-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylicacid

[0652] M.p. 131-134° C. Elemental analysis for C₁₉H₂₃NO₅ Calcd. (%): C,66.07; H, 6.71; N, 4.06. Found (%): C, 65.59; H, 6.69; N, 3.92.

EXAMPLE 282-Methyl-t-5-[3-(5-methyl-2-phenyloxazol-4-yl)propyl]-1,3-dioxane-r-2-carboxylicacid

[0653] M.p. 164-166° C. Elemental analysis for C₁₉H₂₃NO₅ Calcd. (%): C,66.07; H, 6.71; N, 4.06. Found (%): C, 65.64; H, 6.70; N, 3.91.

EXAMPLE 292-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-2-butenyl]-1,3-dioxane-r-2-carboxylicacid

[0654] M.p. 148-150° C. Elemental analysis for C₂₀H₂₃NO₅ Calcd. (%): C,67.21; H, 6.49; N, 3.92. Found (%): C, 67.26; H, 6.36; N, 3.82.

EXAMPLE 302-Methyl-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]benzyl}-1,3-dioxane-2-carboxylicacid

[0655] A mixture (cis:trans=4:1 based on NMR integral value) wasobtained.

[0656] Elemental analysis for C₂₄H₂₅NO₅ Calcd. (%): C, 70.75; H, 6.18;N, 3.44. Found (%): C, 70.69; H, 6.23; N, 3.45.

EXAMPLE 312-Methyl-c-5-{4-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylicacid

[0657] M.p. 215-216° C. Elemental analysis for C₂₃H₂₃NO₅ Calcd. (%): C,70.21; H, 5.89; N, 3.56. Found (%): C, 70.02; H, 5.88; N, 3.35.

EXAMPLE 322-Methyl-c-5-{3-[(5-methyl-2-phenyloxazol-4-yl)methyl]phenyl}-1,3-dioxane-r-2-carboxylicacid

[0658] M.p. 122-124° C. Elemental analysis for C₂₃H₂₃NO₅ Calcd. (%): C,70.21; H, 5.89; N, 3.56. Found (%): C, 70.05; H, 6.08; N, 3.51.

EXAMPLE 332-Methyl-c-5-{4-[5-methyl-2-(3-pyridyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0659] M.p. 126-129° C. Elemental analysis for C₁₉H₂₄N₂O₅ Calcd. (%): C,63.32; H, 6.71; N, 7.77. Found (%): C, 63.16; H, 6.73; N, 7.57.

EXAMPLE 342-Methyl-2-[5-(5-methyl-2-phenyloxazol-4-yl)pentyloxy]propionic acid

[0660] M.p. 66-68° C. Elemental analysis for C₁₉H₂₅NO₄.H₂O Calcd. (%):C, 65.31; H, 7.79; N, 4.01. Found (%): C, 65.20; H, 7.84; N, 4.03.

EXAMPLE 352-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]propionic acid

[0661] Elemental analysis for C₂₀H₂₇NO₄ Calcd. (%): C, 69.54; H, 7.88;N, 4.05. Found (%): C, 69.12; H, 7.86; N, 4.11.

EXAMPLE 362-Methyl-2-[7-(5-methyl-2-phenyloxazol-4-yl)heptyloxy]propionic acid

[0662] M.p. 70-71° C. Elemental analysis for C₂₁H₂₉NO₄ Calcd. (%): C,70.17; H, 8.13; N, 3.90. Found (%): C, 70.03; H, 8.15; N, 3.90.

EXAMPLE 372-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionic acid

[0663] Elemental analysis for C₂₁H₂₉NO₄ Calcd. (%): C, 70.17; H, 8.13;N, 3.90. Found (%): C, 70.07; H, 8.07; N, 3.92.

EXAMPLE 382-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-4-hexynyloxy]propionic acid

[0664] Elemental analysis for C₂₀H₂₃NO₄ Calcd. (%): C, 70.36; H, 6.79;N, 4.10. Found (%): C, 70.24; H, 6.51; N, 3.90.

EXAMPLE 392-{6-[2-(4-Chlorophenyl)-5-methyloxazol-4-yl]hexyloxy}-2-methylpropionicacid

[0665] Elemental analysis for C₂₀H₂₆ClNO₄ Calcd. (%): C, 63.24; H, 6.90;N, 3.69. Found (%): C, 63.17; H, 6.82; N, 3.82.

EXAMPLE 402-{6-[2-(4-Fluorophenyl)-5-methyloxazol-4-yl]hexyl-oxy}-2-methylpropionicacid

[0666] M.p. 64-67° C. Elemental analysis for C₂₀H₂₆FNO₄ Calcd. (%): C,66.10; H, 7.21; N, 3.85. Found (%): C, 66.18; H, 7.30; N, 4.06.

EXAMPLE 412-{6-[2-(4-tert-Butylphenyl)-5-methyloxazol-4-yl]hexyloxy}-2-methylpropionicacid

[0667] M.p. 89-91° C. Elemental analysis for C₂₄H₃₅NO₄ Calcd. (%): C,71.79; H, 8.79; N, 3.49. Found (%): C, 71.79; H, 8.81; N, 3.52.

EXAMPLE 42 2-[6-(5-Ethyl-2-phenyloxazol-4-yl)hexyloxy]-2-methylpropionicacid

[0668] M.p. 88.5-89° C. Elemental analysis for C₂₁H₂₉NO₄ Calcd. (%): C,70.17; H, 8.13; N, 3.90. Found (%): C, 70.36; H, 8.07; N, 3.90.

EXAMPLE 43 2-Methyl-2-[6-(2-phenyloxazol-4-yl)hexyloxy]propionic acid

[0669] M.p. 75-77° C. Elemental analysis for C₁₉H₂₅NO₄ Calcd. (%): C,68.86; H, 7.60; N, 4.23. Found (%): C, 68.89; H, 7.62; N, 4.27.

EXAMPLE 44 2-Methyl-2-[7-(2-phenyloxazol-4-yl)heptyloxy]propionic acid

[0670] M.p. 72-75° C. Elemental analysis for C₂₀H₂₇NO₄ Calcd. (%): C,69.54; H, 7.88; N, 4.05. Found (%): C, 69.67; H, 7.89; N, 4.06.

EXAMPLE 45 2-Methyl-2-[8-(2-phenyloxazol-4-yl)octyloxy]propionic acid

[0671] M.p. 59-61° C. Elemental analysis for C₂₁H₂₉NO₄ Calcd. (%): C,70.17; H, 8.13; N, 3.90. Found (%): C, 70.02; H, 8.30; N, 3.91.

EXAMPLE 462-{7-[2-(4-Chlorophenyl)oxazol-4-yl]heptyloxy}-2-methylpropionic acid

[0672] M.p. 91-93° C. Elemental analysis for C₂₀H₂₆ClNO₄ Calcd. (%): C,63.24; H, 6.90; N, 3.69. Found (%): C, 63.39; H, 6.98; N, 3.72.

EXAMPLE 472-{7-[2-(4-Fluorophenyl)oxazol-4-yl]heptyloxy}-2-methylpropionic acid

[0673] M.p. 67-74° C. Elemental analysis for C₂₀H₂₆FNO₄ Calcd. (%): C,66.10; H, 7.21; N, 3.85. Found (%): C, 65.90; H, 7.06; N, 3.84.

EXAMPLE 482-{6-[2-(4-Fluorophenyl)oxazol-4-yl]hexyloxy}-2-methylpropionic acid

[0674] M.p. 80-83° C. Elemental analysis for C₁₉H₂₄FNO₄ Calcd. (%): C,65.31; H, 6.92; N, 4.01. Found (%): C, 65.15; H, 6.77; N, 3.91.

EXAMPLE 49 2-Methyl-2-[7-(2-phenylthiazol-4-yl)heptyloxy]propionic acid

[0675] M.p. 71-72° C. Elemental analysis for C₂₀H₂₇NO₃S Calcd. (%): C,66.45; H, 7.53; N, 3.87. Found (%): C, 66.46; H, 7.57; N, 3.98.

EXAMPLE 50 2-Methyl-2-[8-(2-phenylthiazol-4-yl)octyloxy]propionic acid

[0676] M.p. 64-70° C. Elemental analysis for C₂₁H₂₉NO₃S .H₂O Calcd. (%):C, 64.09; H, 7.94; N, 3.56. Found (%): C, 64.67; H, 7.89; N, 3.83.

EXAMPLE 512-Methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionic acid

[0677] M.p. 91-93° C. Elemental analysis for C₁₉H₂₆N₂O₄ Calcd. (%): C,65.88; H, 7.56; N, 8.09. Found (%): C, 65.79; H, 7.52; N, 8.03.

EXAMPLE 522-Methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propionic acid

[0678]¹H-NMR (CDCl₃)δ: 1.25-1.50 (10H, m), 1.55-1.75 (4H, m), 2.34 (3H,s), 2.50 (2H, t), 3.45 (2H, t), 7.35-7.42 (1H, m), 8.26-8.30 (1H, m),8.62-8.66 (1H, m), 9.21-9.22 (1H, m).

EXAMPLE 532-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)-(E)-3-butenyl]-1,3-dioxane-r-2-carboxylicacid

[0679] Methyl2-methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylate(7.5 g) was dissolved in 30 ml of N,N-dimethylformamide, and a solutionof 3.57 g of N-bromosuccinimide (NBS)/20 ml of N,N-dimethylformamide wasadded dropwise with stirring under ice-cooling. After30-minute-stirring, the reaction solution was poured into ice-cold waterand extracted with ethyl acetate. The organic layer was washed withbrine, dried over anhydrous magnesium sulfate and concentrated. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane: ethyl acetate=7:1) to provide 215 mg of oil. Theresulting oil was dissolved in 3 ml of methanol. To the solution wereadded 70 mg of sodium hydroxide and 0.8 ml of water, and the mixture wasrefluxed for 2.5 hours, and concentrated. After addition of ice, theresidue was acidified with 1 N hydrochloric acid, extracted with ethylacetate, washed with brine, dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, ethyl acetate) to provide 30 mg of theobjective compound.

[0680]¹H-NMR (CDCl₃)δ: 1.22 (2H, ddd), 1.65 (3H, s), 2.00-2.30 (3H, m),2.38 (3H, s), 3.51 (2H, dd), 4.02 (2H, dd), 4.20 (1H, br), 6.15-6.40(2H, m), 7.40-7.60 (3H, m), 7.90-8.20 (2H, m).

EXAMPLE 54 Potassium2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenyloxy]propionate

[0681] To 20 ml of a solution of 920 mg of methyl2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenyloxy]-2-methylpropionate in methanol, 20 ml of an aqueous solution of 206 mg of sodiumhydroxide was added, and heated to reflux for 20 hours. The reactionsolution was concentrated. After addition of ice-cold water, the residuewas acidified with 10% hydrochloric acid. The mixture was extracted withethyl acetate, washed with water, dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel column chromatography (Wakogel®C-200, chloroform) to provide 670 mg of2-[6-(5-methyl-2-phenyloxazol-4-yl)-(E)-4-hexenyloxy]-2-methyl propionicacid as colorless oil. A portion (100 mg) of the oil was converted intopotassium salt with potassium hydroxide. After addition of isopropylether, the precipitates were collected by filtration to provide 88 mg ofthe objective compound.

[0682] Elemental analysis for C₂₀H₂₄NO₄K.1/2H₂O Calcd. (%): C, 61.51; H,6.45; N, 3.59. Found (%): C, 61.56; H, 6.24; N, 3.53.

EXAMPLE 552-Methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]-propanol

[0683] To 214 ml of dry ether, 1.35 g of lithium aluminum hydride wasadded, and a solution of 10.7 g of methyl2-methyl-2-[6-(5-methyl-2-phenyloxazol-4-yl)hexyloxy]-propionate/40 mlof dry ether was added dropwise with stirring under ice-cooling andstirred for 1 hour. To the mixture was added dropwise 43 ml oftetrahydrofuran/1.7 ml of water followed by addition of 6.3 ml of waterand 1.7 ml of 1 N sodium hydroxide, and the mixture was stirred for 15minutes and filtrated to remove insolubles. The filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide8.44 g of the objective compound. Elemental analysis forC₂₀H₂₉NO₃.1/2H₂O Calcd. (%): C, 70.55; H, 8.88; N, 4.11. Found (%): C,70.95; H, 8.67; N, 4.21.

[0684] The compounds of Examples 56-58 were prepared by the sameprocedure as described in Example 55.

EXAMPLE 562-{6-[2-(4-tert-Butylphenyl)-5-methyloxazole-4-yl]-hexyloxy}-2-methylpropanol

[0685]¹H-NMR (CDCl₃)δ: 1.14 (6H, s), 1.34-1.43 (11H, m), 1.45-1.75 (6H,m), 1.95-2.10 (1H, m), 2.31 (3H, s), 2.47 (2H, t), 3.30-3.41 (4H, m),7.41-7.45 (2H, m), 7.88-7.92 (2H, m). Elemental analysis forC₂₄H₃₇NO₃.H₂O Calcd. (%): C, 71.07; H, 9.69; N, 3.45. Found (%): C,70.89; H, 9.32; N, 3.20.

EXAMPLE 572-Methyl-2-{6-[5-methyl-2-(3-pyridyl)oxazol-4-yl]hexyloxy}propanol

[0686]¹H-NMR (CDCl₃)δ: 1.15 (6H, s), 1.34-1.40 (4H, m), 1.45-1.85 (4H,m), 1.95-2.10 (1H, m), 2.34 (3H, s), 2.45 (2H, t), 3.31-3.40 (4H, m),7.27-7.36 (1H, m), 8.22-8.28 (1H, m), 8.61-8.64 (1H, m), 9.20-9.21 (1H,m). Elemental analysis for C₁₉H₂₈N₂O₃.H₂O Calcd. (%): C, 65.12; H, 8.63;N, 7.99. Found (%) : C, 65.24; H, 8.40; N, 7.73.

EXAMPLE 58r-2-Hydroxymethyl-2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane

[0687] M.p. 58-59° C. Elemental analysis for C₂₁H₂₉NO₄ Calcd. (%): C,70.17; H, 8.13; N, 3.90. Found (%): C, 69.97; H, 8.05; N, 3.88.

EXAMPLE 592-Methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propanolmethansulfonatesalt

[0688] Methyl2-methyl-2-{6-[5-methyl-2-(4-pyridyl)oxazol-4-yl]hexyloxy}propionate(210 mg) was dissolved in 20 ml of dry ether, and 44 mg of lithiumaluminum hydride was added and stirred for 30 minutes under ice-cooling.Then, 5 ml of tetrahydrofuran/0.33 ml of water was added dropwise,stirred for 15 minutes and filtrated to remove insolubles, and thefiltrate was concentrated. The residue was dissolved into ether. To thesolution was added 59 mg of methanesulfonic acid/1 ml of ether, andfiltered to collect precipitated crystals, which were washed with etherand dried to provide 195 mg of the objective compound as pale yellowcrystals. M.p. 128-130° C.

[0689] Elemental analysis for C₁₉H₂₈N₂O₃.CH₄O₃S.H₂O Calcd. (%): C,53.79; H, 7.67; N, 6.27. Found (%): C, 53.87; H, 7.28; N, 6.17.

EXAMPLE 602-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carbohydroxamicacid

[0690]2-Methyl-c-5-[4-(5-methyl-2-phenyloxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylicacid (350 mg) was dissolved in 7.5 ml of tetrahydrofuran, and 174 mg of1,1′-

[0691] M.p. 118-119° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 68.20; H, 7.53; N, 3.60.

EXAMPLE 632-Ethyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]-butyl}-1,3-dioxane-r-2-carboxylicacid

[0692] M.p. 123-126° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 69.22; H, 7.53; N, 3.21.

EXAMPLE 642-Methyl-c-5-{4-[5-methyl-2-(3-fluoro-4-methylphenyl)-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0693] Elemental analysis for C₂₁H₂₆FNO₅ Calcd. (%): C, 64.44; H, 6.69;N, 3.58. Found (%): C, 64.49; H, 6.68; N, 3.90.

EXAMPLE 652-Methyl-c-5-{4-[5-methyl-2-(4-ethylphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0694] M.p. 147° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 67.99; H, 7.50; N, 3.76.

EXAMPLE 662-Methyl-c-5-{4-[2-(p-tolyl)-5-trifluoromethyloxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0695] M.p. 130-131° C. Elemental analysis for C₂₁H₂₄F₃NO₅ Calcd. (%):C, 59.01; H, 5.66; N, 3.28. Found (%): C, 59.11; H, 5.67; N, 3.16.

EXAMPLE 672-Methyl-c-5-{4-[5-methyl-2-(2,4-dimethylphenyl)-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0696] M.p. 130-131° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 68.25; H, 7.53; N, 3.65.

EXAMPLE 682-Methyl-c-5-{4-[2-(4-fluoromethylphenyl)-5-methyloxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0697] M.p. 144-145° C. Elemental analysis for C₂₁H₂₆-FNO₅ Calcd. (%):C, 64.44; H, 6.69; N, 3.58. Found (%): C, 64.35; H, 6.69; N, 3.52.

EXAMPLE 692-Methyl-c-5-{4-[5-ethyl-2-(p-tolyl)oxazol-4-yl]-butyl}-1,3-dioxane-r-2-carboxylicacid

[0698] M.p. 160-161° C. Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C,68.20; H, 7.54; N, 3.61. Found (%): C, 68.15; H, 7.52; N, 3.56.

EXAMPLE 702-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)thiazol-4-yl]-butyl}-1,3-dioxane-r-2-carboxylicacid

[0699] Elemental analysis for C₂₁H₂₇NO₄S Calcd. (%): C, 64.76; H, 6.99;N, 3.60. Found (%): C, 64.68; H, 6.97; N, 3.64.

EXAMPLE 712-Methyl-c-5-{4-[5-methyl-2-(m-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0700] Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C, 67.54; H, 7.29;N, 3.75. Found (%): C, 67.57; H, 7.22; N, 3.80.

EXAMPLE 722-Methyl-c-5-{4-[5-methyl-2-(o-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0701] M.p. 121-122° C. Elemental analysis for C₂₁H₂₇NO₅ Calcd. (%): C,67.54; H, 7.29; N, 3.75. Found (%): C, 67.47; H, 7.29; N, 3.71.

EXAMPLE 732-Methyl-c-5-{4-[5-methyl-2-(3,4-dimethylphenyl)-oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0702] Elemental analysis for C₂₂H₂₉NO₅ Calcd. (%): C, 68.20; H, 7.54;N, 3.61. Found (%): C, 68.31; H, 7.53; N, 3.65.

EXAMPLE 742-Methyl-c-5-{4-[5-methyl-2-(4-methoxyphenyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0703] Elemental analysis for C₂₁H₂₇NO₆ Calcd. (%): C, 64.77; H, 6.99;N, 3.60Found (%): C, 64.80; H, 7.13; N, 3.57.

EXAMPLE 752-Methyl-c-5-{4-[5-methyl-2-(2-thienyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0704] Elemental analysis for C₁₈H₂₃NO₅S Calcd. (%): C, 59.16; H, 6.34;N, 3.83. Found (%): C, 59.45; H, 6.32; N, 3.76.

EXAMPLE 762-Methyl-c-5-{4-[2-cyclohexyl-5-methyloxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0705] M.p. 118-121° C. Elemental analysis for C₂₀H₃₁NO₅ Calcd. (%): C,65.73; H, 8.55; N, 3.83. Found (%): C, 65.75; H, 8.57; N, 3.80.

EXAMPLE 772-Methyl-c-5-{4-[1,5-dimethyl-2-(p-tolyl)imidazole-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid

[0706] M.p. 192-194° C. (decomposed). Elemental analysis forC₂₂H₃₀N₂O₄.1H₂O Calcd. (%): C, 65.32; H, 7.97; N, 6.93. Found (%): C,65.36; H, 7.58; N, 6.75.

EXAMPLE 78 Methyl2-methyl-c-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylate

[0707]2-[3-{[5-Methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-propanediol(2.29 g) was dissolved in 38 ml of acetonitrile, and 2.65 g of methylpyruvate was added. To the mixture, 3.69 g of boron trifluoride etherate(about 47% ) was added with stirring at room temperature, and stirredfor 18 hours at room temperature. The reaction solution was poured intoan aqueous solution of sodium hydrogencarbonate, and extracted withethyl acetate. The organic layer was washed with water, dried overanhydrous magnesium sulfate and concentrated. The residue was purifiedby silica gel column chromatography (Wakogel® C-200, n-hexane: ethylacetate=4:1) and the fractions eluted earlier were concentrated toprovide 752 mg g of the objective compound as colorless oil.

[0708]¹H-NMR (CDCl₃)δ: 1.49 (3H, s), 2.20-2.35 (3H, m), 2.25 (3H, s),2.38 (3H, s), 3.48 (2H, t), 3.80-3.95 (4H, m), 3.83 (3H, s), 6.92-7.24(6H, m), 7.80-7.90 (2H, m).

EXAMPLE 79 Methyl2-methyl-t-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylate

[0709] The latter fractions of Example 78 were collected andconcentrated to provide 294 mg of the objective compound as colorlessoil.

[0710]¹H-NMR (CDCl₃)δ: 1.57 (3H, s), 2.20-2.35 (1H, m), 2.25 (3H, s),2.38 (3H, s), 2.98 (2H, d), 3.70-3.88 (4H, m), 3.82 (3H, s), 3.93 (2H,dd), 7.00-7.30 (6H, m), 7.87 (2H, d).

EXAMPLE 802-Methyl-c-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]-methyl}benzyl]-1,3-dioxane-r-2-carboxylicacid

[0711] To 20 ml of methanol, 968 mg of methyl2-methyl-c-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylatewas dissolved. After addition of 3.3 ml of aqueous 1 N sodium hydroxidesolution, the mixture was heated to reflux for 1.5 hours. The reactionsolution was concentrated. The residue was, after addition of water,washed with diethyl ether. The aqueous layer was acidified with 1 Nhydrochloric acid and extracted with diethyl ether, dried over anhydrousmagnesium sulfate and concentrated. The residue was crystallized byadding diethyl ether, and washed with isopropyl ether to provide 733 mgof the objective compound as colorless crystals.

[0712] M.p. 151-152° C. Elemental analysis for C₂₅H₂₇NO₅ Calcd. (%): C,71.24; H, 6.46; N, 3.32. Found (%): C, 71.50; H, 6.42; N, 3.48.

EXAMPLE 812-Methyl-t-5-[3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl]-1,3-dioxane-r-2-carboxylicacid

[0713] The objective compound was prepared by the same procedure asExample 80.

[0714] Elemental analysis for C₂₅H₂₇NO₅ Calcd. (%): C, 71.24; H, 6.46;N, 3.32. Found (%): C, 70.18; H, 6.34; N, 3.31.

EXAMPLE 822-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dithiane-r-2-carboxylicacid

[0715] To 2 ml of a solution of 124 mg of methyl2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]-butyl}-1,3-dithiane-r-2-caroxylatein methanol, 1 ml of aqueous solution of 1 N sodium hydroxide was added,and heated to reflux for 1.5 hours. The reaction solution wasconcentrated. The residue was, after addition of water, washed withdiethyl ether. The aqueous layer was acidified with 1N hydrochloricacid, extracted with ethyl acetate, dried over anhydrous magnesiumsulfate and concentrated. The residue was crystallized by addingisopropyl ether, and washed with n-hexane to provide 88 mg of theobjective compound as colorless crystals.

[0716] M.p. 157-159° C. Elemental analysis for C₂₁H₂₇NO₃S₂ Calcd. (%):C, 62.19; H, 6.71; N, 3.45. Found (%): C, 61.93; H, 6.70; N, 3.40.

EXAMPLE 832-Methyl-t-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dithiane-r-2-carboxylicacid

[0717] The objective compound was prepared by the same procedure asExample 82.

[0718] M.p. 162-164° C. Elemental analysis for C₂₁H₂₇NO₃S₂ Calcd. (%):C, 62.19; H, 6.71; N, 3.45. Found (%): C, 61.75; H, 6.66; N, 3.42.

EXAMPLE 842-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyl-thio}propionic acid

[0719] Under argon atmosphere, 24 mg of triturated sodium hydroxide wasadded to 2 ml of a solution of 100 mg of4-(6-acetylthiohexyl)-5-methyl-2-(p-tolyl)oxazole in acetone, andstirred for 2 hours at room temperature. To the reaction solution, 20 μlof water was added, followed by addition of 113 mg of1,1,1-trichloro-2-methyl-2-propanol.0.5 hydride (chloretone), and then96.5 mg of triturated sodium hydroxide in tree portions at 30 minutesintervals. The mixture was stirred for additional 18 hours at roomtemperature. The reaction solution was concentrated. The residue was,after addition of water, extracted with diethyl ether. The organiclayers were combined, washed with water, and the washings was acidifiedwith 1 N hydrochloric acid and extracted with ethyl acetate. The organiclayers were combined, washed with water and brine sequentially, driedover anhydrous magnesium sulfate, and the solvent was distilled offunder reduced pressure. The residue was purified by silica gel columnchromatography (Wakogel® C-200, chloroform:methanol=100:1) and theresulting crystals were washed with n-hexane to provide 28.0 mg of theobjective compound as pale yellow crystals.

[0720] M.p. 111° C. Elemental analysis for C₂₁H₂₉NO₃S₂ Calcd. (%): C,67.17; H, 7.78; N, 3.73. Found (%): C, 67.33; H, 7.85; N, 3.67.

EXAMPLE 852-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]-hexyloxy}propiononitrile

[0721] Phosphorus tribromide (6.77 g) was added to 94 ml of a solutionof 4.90 g of2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionohydroxamicacid in benzene, and heated to reflux for 4 hours. The reaction solutionwas cooled, poured into ice-cold water. After addition of saturatedaqueous sodium hydrogencarbonate solution, the mixture was extractedwith ethyl acetate. The organic layer was washed with water and brinesequentially, dried over anhydrous magnesium sulfate and concentrated.The residue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=9:1) to provide 3.32 g of the objectivecompound as a colorless crystals. M.p. 36° C.

[0722] Elemental analysis for C₂₁H₂₈N₂O₂.1/5H₂O Calcd. (%): C, 73.31; H,8.32; N, 8.14. Found (%): C, 73.21; H, 8.27; N, 7.88.

EXAMPLE 865-[l-Methyl-l-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}ethyl]tetrazole

[0723] Sodium azide (4.12 g) and 2.97 g of ammonium chloride were addedto 27 ml of a solution of 2.70 g of2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}-propiononitrilein N,N-dimethylformamide, and stirred for 1.5 hours at 120° C. To thereaction solution was added ice-cold water, and extracted with ethylacetate, washed with water and brine sequentially, dried over anhydrousmagnesium sulfate and concentrated. The residue was purified by silicagel column chromatography (Wakogel® C-200, chloroform:methanol=100:1 to50:1) and recrystallized from isopropyl ether to provide 1.69 g of theobjective compound as colorless crystals. M.p. 87° C.

[0724] Elemental analysis for C₂₁H₂₉N₅O₂ Calcd. (%): C, 65.77; H, 7.62;N, 18.26. Found (%): C, 65.67; H, 7.65; N, 17.97.

EXAMPLE 872-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxyamide

[0725] Under argon atmosphere, 45 ml of a solution of 3.00 g of2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylicacid in tetrahydrofuran was cooled with ice and 1.12 ml oftriethylamine, and then 5 ml of a solution of 959 mg of ethylchloroformate in tetrahydrofuran were added dropwise. After45-minute-stirring, 45 ml of ammonia-saturated tetrahydrofuran was addeddropwise, and stirred for additional 1 hour. To the reaction solutionwas added water, and extracted with ethyl acetate, washed with saturatedsodium hydrogencarbonate and water sequentially and dried over anhydrousmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting crystals were washed with diethyl ether to provide2.81 g of the objective compound as colorless crystals. M.p. 146-147° C.

[0726] Elemental analysis for C₂₁H₂₈N₂O₄ Calcd. (%): C, 67.72; H, 7.58;N, 7.52. Found (%): C, 67.26; H, 7.54; N, 7.39.

EXAMPLE 882-Methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]-butyl}-1,3-dioxane-r-2-carbonitrile

[0727] Under argon atmosphere, 2.04 ml of triethylamine was

[0728] added dropwise to 34 ml of a solution of 2.27 g of2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dioxane-r-2-carboxyamidein tetrahydrofuran. After 10-minute-stirring under ice-cooling, 5 ml ofa solution of 1.53 g of trifluoroacetic anhydride in tetrahydrofuran wasadded drowse slowly, and stirred additional 1 hour. To the reactionsolution was added water, and extracted with diethyl ether, washed withsaturated sodium hydrogen carbonate and water sequentially, dried overanhydrous magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel column chromatography(Wakogel® C-200, n-hexane:ethyl acetate=4:1) to provide 2.07 g of theobjective compound as colorless crystals. M.p. 79-80° C.

[0729] Elemental analysis for C₂₁H₂₆N₂O₃ Calcd. (%): C, 71.16; H, 7.39;N, 7.90. Found (%): C, 71.01; H, 7.42; N, 7.90.

EXAMPLE 89 Methyl2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dithine-r-2-carboxylate

[0730] To 20 ml of a solution of 635 mg of4-[5,5-bis(mercaptomethyl)pentyl]-5-methyl-2-(p-tolyl)oxazole inacetonitrile, 0.344 ml of methyl pyruvate and 0.48 ml of borontrifluoride etherate (about 47% ) were added, and heated to reflux for 2hours. The reaction solution was cooled, poured into ice-cold water andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography (Wakogel® C-200,n-hexane:ethyl acetate=9:1) and the fractions eluted earlier wereconcentrated to provide 124 mg of the objective compound as colorlessoil.

[0731]¹H-NMR (CDCl₃)δ: 1.25-1.55 (4H, m), 1.69 (3H, s), 1.70-1.90 (3H,m), 2.31 (3H, s), 2.38 (3H, s), 2.40-2.60 (4H, m), 3.54 (2H, m), 3.77(3H, s), 7.22 (2H, s), 7.86 (2H, s).

EXAMPLE 90 Methyl2-methyl-t-5-{4-[5-methyl-2-(p-tolyl)oxazol-4-yl]butyl}-1,3-dithiane-r-2-carboxylate

[0732] The latter fractions of Example 89 were collected andconcentrated to provide 124 mg of the objective compound as colorlessoil.

[0733]¹H-NMR (CDCl₃)δ: 1.30-1.50 (4H, m), 1.55-1.90 (7H, m), 2.31 (3H,s), 2.38 (3H, s), 2.47 (2H, t), 2.58 (2H, dd), 3.07 (2H, dd), 3.11 (2H,s), 7.23 (2H, d), 7.87 (2H, d).

EXAMPLE 912-Methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionohydroxamicacid

[0734] To 20 ml of a solution of 4.84 g of ethyl2-methyl-2-{6-[5-methyl-2-(p-tolyl)oxazol-4-yl]hexyloxy}propionate inmethanol, 3.47 g of hydroxylammonium chloride was added, and then 12.5ml of solution of 5 M potassium hydroxide in methanol was added dropwiseslowly under ice-cooling with stirring. The ice-bath was removed and themixture was stirred for 36 hours at room temperature. The reactionsolution was concentrated. The residue was acidified with 50% aqueousacetic acid solution, water was added thereto and extracted with ethylacetate. The organic layer was washed with water and brine serially,dried over anhydrous magnesium sulfate and concentrated. The residue wasconcentrated after addition of toluene, and again concentrated afteraddition of ethanol to provide 4.90 g of the objective compound as paleyellow oil.

[0735]¹H-NMR (CDCl₃)δ: 1.36-1.41 (4H, m), 1.38 (6H, s), 1.53-1.70 (4H,m), 2.31 (3H, s), 2.38 (3H, s), 2.48 (2H, t), 3.37 (2H, t), 7.23 (2H,d), 7.87 (2H, d).

EXAMPLE 92 Methyl2-methyl-c-5-{4-[1,5-dimethyl-2-(p-tolyl)imidazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

[0736] To 20 ml of a solution of 0.80 g of methylc-5-[5-acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylatein xylene, 1.5 ml of a solution of 2 M methylamine in tetrahydrofuranand 0.84 ml of acetic acid were added. The mixture was subjected toazeotropic dehydration with Dean-Stark apparatus for 2 hours. Thereaction solution was cooled, poured into aqueous sodium hydrogencarbonate, extracted with ethyl acetate, dried over anhydrous magnesiumsulfate and concentrated. The residue was purified by silica gel columnchromatography (Wakogel® C-200, chloroform:methanol=100:1) to provide634 mg of the objective compound as pale yellow oil.

[0737]¹H-NMR (CDCl₃)δ: 0.97-1.10 (2H, m), 1.20-1.40 (2H, m), 1.50 (3H,s), 1.54-1.70(2H, m), 1.90-2.15 (1H, m), 2.18 (3H, s), 2.38 (3H, s),2.51 (2H, t), 3.38 (2H, t), 3.53 (3H, s), 3.83 (3H, s), 3.95 (2H, dd),7.23 (2H, dd), 7.45 (2H, dd).

EXAMPLE 93 Methyl2-methyl-c-5-{4-[5-methyl-2-(p-tolyl)thiazol-4-yl]butyl}-1,3-dioxane-r-2-carboxylate

[0738] To 10 ml of tetrahydrofuran, 1.01 g of methylc-5-[5-acetyl-5-(p-toluoylamino)pentyl]-2-methyl-1,3-dioxane-r-2-carboxylatewas dissolved. After addition of 1.42 g of2,4-bis(methylthio)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Davyreagent methyl), the mixture was stirred for 3 hours at 50-55° C. andadditional 3 hours at 70-75° C. To the reaction solution was added ethylacetate, and washed with 10% hydrochloric acid, water and 10% sodiumhydroxide sequentially, dried over magnesium sulfate and concentrated.The residue was purified by silica gel column chromatography (Wakogel®C-200, n-hexane:ethyl acetate=5:1) to provide 384 mg of the objectivecompound as pale yellow oil.

[0739]¹H-NMR (CDCl₃)δ: 1.00-1.15 (2H, m), 1.23-1.40 (2H, m), 1.51 (3H,s), 1.60-1.77 (2H, m), 1.92-2.14 (1H, m), 2.37 (6H, s), 2.66 (2H, t),3.39 (2H, t), 3.83 (3H, s), 3.95 (2H, dd), 7.20 (2H, d), 7.75 (2H, d).

Experimental Example 1

[0740] Effects on carbohydrate and lipid metabolism in KK-A^(y) Mouse

[0741] The experiment was conducted using the compounds described in theExamples as test compounds and Troglitazone(5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-thiazolidinedione)as a control compound.

[0742] Each test compound was orally administered to KK-A^(y) mice (10week old, male), NIDDM model animal, for 4 days at a given dosage. Onthe next day of the last administration, blood was collected from tailend blood vessels under non-fasting conditions to prepare heparinizedplasma. Thereafter, blood was collected from an abdominal large veinunder pentobarbital anesthesia to prepare serum. The glucose level (BG),triglyceride level (TG) and insulin level (Ins) in plasma were measuredusing a glucose CII-test WACO (Wako Pure Chemical Industries, Ltd),CLINTECH TG-S (IATORON LABORATORIES, INC.) or triglyceride E-test WAKO(Wako Pure Chemical Industries, Ltd), and a rat insulin measurement kit(Morinaga Biochemistry Research Institute) or REBIS-insulin-mouse-T(Mouse Insulin ELISA (TMB) KIT, Shibayagi Co.,Ltd), respectively. Also,the sum of VLDL-C level and LDL-C level in serum (hereinafter, referredto as “(V)LDL-C”), total cholesterol level (TC) and HDL-C level weremeasured using a high performance liquid chromatography system for themeasurement of lipoprotein cholesterol (TOSOH CORPORATION). (V)LDL-Clevel was measured because VLDL-C and LDL-C cannot be measuredseparately. Atherogenic Index (AI) was calculated according to thefollowing formula:

AI=[(TC level)−(HDL-C level)]/(HDL-C level).

[0743] The results are shown in Table 1. TABLE 1 Effects on carbohydrateand lipid metabolism of KK-A^(y) mice Dose Percent change of eachparameter Test (mg/ compared to control group (%) compound kg) TG BG Ins(V) LDL-C HDL-C AI Example 39 1 −56 −14 −20 −53 36 −73 Example 14 1 −29−22 −67 −38 19 −45 Example 9 1 −46 −12 −36 −29 36 −49 Example 54 1 −72−24 −14 −77 24 −83 Example 38 1 −50 −21 −39 −38 38 −65 Example 21 3 −52−18 −26 −26 5 −38 Example 20 1 −31 −15 −44 −33 30 −44 Example 53 3 −51−46 −37 −49 3 −62 Example 18 3 −43 −12 −1 −20 76 −65 Example 55 10 −45−22 2 −44 62 −72 Example 37 3 −51 −5 −27 −54 33 −70 Example 11 3 −83 −36−16 −89 11 −91 Example 81 1 −62 −8 −21 −76 32 −83 Example 64 1 −53 −12−20 −63 21 −72 Example 70 3 −37 −15 5 −33 41 −53 Example 71 3 −89 −51−61 −90 1 −90 Example 73 3 −92 −53 −68 −90 −8 −85 Example 74 3 −46 −18−33 −58 55 −72 Example 75 3 −47 −23 −29 −50 37 −61 Troglitazone 300 −11−9 −22 −26 −8 −7

[0744] The present compounds showed excellent blood triglyceridelowering effect and (V)LDL-C lowering effect. Furthermore, the presentcompounds showed blood glucose lowering effect, blood insulin loweringeffect or HDL-C increasing effect or atherogenic index lowering effect.It is clear that the present compounds are useful as a preventive ortherapeutic agent for arteriosclerosis, and the like.

Formulation Example 1

[0745] Tablet (for oral administration) Formulation per a tablet (200mg) Compound of Example 71 20 mg Cornstarch 88 mg Crystalline cellulose80 mg Carboxymethyl cellulose calcium 10 mg Light silicic acid anhydride 1 mg Magnesium stearate  1 mg

[0746] A mixture containing the ingredients of the ratio above iscompressed to form a tablet for oral administration.

Formulation Example 2

[0747] Tablet (for oral administration) Formulation per a tablet (120mg) Compound of Example 11  1 mg Lactose 60 mg Cornstarch 30 mgCrystalline cellulose 20 mg Hydroxypropylcellulose  7 mg Magnesiumstearate  2 mg

[0748] A mixture containing the ingredients of the ratio above iscompressed to form a tablet for oral administration.

Formulation Example 3

[0749] Tablet (for oral administration) Formulation per a tablet (180mg) Compound of Example 73 100 mg  Lactose 45 mg  Cornstarch 20 mg Low-substituted hydroxypropylcellulose 9 mg Polyvinyl alcohol (partiallysaponified) 5 mg Magnesium stearate 1 mg

[0750] A mixture containing the ingredients of the ratio above iscompressed to form a tablet for oral administration.

Industrial Applicability

[0751] The present compounds have excellent blood triglyceride loweringeffect, (V)LDL-C lowering effect, and blood glucose lowering effect,blood insulin lowering effect, or HDL-C increasing effect or atherogenicindex lowering effect all together, and hence is useful in theprevention or treatment of coronary artery diseases, cerebralinfarction, hyperlipidemia, arteriosclerosis, diabetes mellitus,hypertension, obesity, and the like.

1. A heterocyclic compound of the formula [1], or a pharmaceuticallyacceptable salt thereof: R¹-Het-D-E  [1] wherein: R¹ is aryl; said arylbeing optionally substituted by the same or different one to threegroups selected from alkyl, haloalkyl, trihaloalkyl, alkoxy, halogen andnitro; E is a group of the formula [3]:

wherein Y is oxygen or sulfur; R³ is hydrogen or alkyl; p is an integerof 0-2; Z is carboxy, alkoxycarbonyl, hydroxymethyl, carbamoyl,N-hydroxycarbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, cyano,1H-5-tetrazolyl, 1-alkyl-5-tetrazolyl, or 2-alkyl-5-tetrazolyl; Het andD correspond to any one of the following cases (1) to (2) (1) Het is athiazole which is optionally substituted by alkyl or trihaloalkyl; D isalkylene, alkenylene, or alkynylene; and (2) Het is an oxazole which isoptionally substituted by alkyl or trihaloalkyl; and D is a group of theformula [2]:

wherein m is an integer of 1-10 and n is an integer of 0-9, with theproviso that m+n is an integer of 1-10.
 2. A therapeutic pharmaceuticalcomposition for hyperlipidemia, comprising as an active ingredient aheterocyclic compound as set forth in claim 1, or a pharmaceuticallyacceptable salt thereof:
 3. A therapeutic pharmaceutical composition forarteriosclerosis, comprising as an active ingredient a heterocycliccompound as set forth in claims 1, or a pharmaceutically acceptable saltthereof.
 4. A therapeutic pharmaceutical composition for ischemic heartdisease, comprising as an active ingredient a heterocyclic compound asset forth claim 1, or a pharmaceutically acceptable salt thereof.
 5. Atherapeutic pharmaceutical composition for cerebral infarction,comprising as an active ingredient a heterocyclic compound as set forthin claim 1, or a pharmaceutically acceptable salt thereof.
 6. Atherapeutic pharmaceutical composition for reocclusion after PTCA,comprising as an active ingredient a heterocyclic compound as set forthin claim 1, or a pharmaceutically acceptable salt thereof.
 7. Atherapeutic pharmaceutical composition for diabetes mellitus, comprisingas an active ingredient a heterocyclic compound as set forth in claim 1,or a pharmaceutically acceptable salt thereof.
 8. A therapeuticpharmaceutical composition for obesity, comprising as an activeingredient a heterocyclic compound as set forth in claim 1, or apharmaceutically acceptable salt thereof.